U.S. patent application number 14/091593 was filed with the patent office on 2014-03-27 for phosphoramide compound, method for producing the same, ligand, complex, catalyst and method for producing optically active alcohol.
This patent application is currently assigned to Sekisui Medical Co., Ltd.. The applicant listed for this patent is National University Corporation Nagoya University, Sekisui Medical Co., Ltd.. Invention is credited to Manabu HATANO, Kazuaki ISHIHARA, Takashi MIYAMOTO.
Application Number | 20140088303 14/091593 |
Document ID | / |
Family ID | 39759314 |
Filed Date | 2014-03-27 |
United States Patent
Application |
20140088303 |
Kind Code |
A1 |
ISHIHARA; Kazuaki ; et
al. |
March 27, 2014 |
PHOSPHORAMIDE COMPOUND, METHOD FOR PRODUCING THE SAME, LIGAND,
COMPLEX, CATALYST AND METHOD FOR PRODUCING OPTICALLY ACTIVE
ALCOHOL
Abstract
Disclosed is a method for highly efficiently obtaining an
optically active alcohol from a carbonyl compound highly
enantioselectively. Also disclosed is a ligand used in such a
method. Specifically, an optically active alcohol is obtained by
reacting a carbonyl compound and an organozinc compound by using a
ligand (L) shown below. ##STR00001##
Inventors: |
ISHIHARA; Kazuaki;
(Nagoya-shi, JP) ; HATANO; Manabu; (Nagoya-shi,
JP) ; MIYAMOTO; Takashi; (Nagoya-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sekisui Medical Co., Ltd.
National University Corporation Nagoya University |
Chou-ku
Nagoya-shi |
|
JP
JP |
|
|
Assignee: |
Sekisui Medical Co., Ltd.
Chou-ku
JP
National University Corporation Nagoya University
Nagoya-shi
JP
|
Family ID: |
39759314 |
Appl. No.: |
14/091593 |
Filed: |
November 27, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13458400 |
Apr 27, 2012 |
8624024 |
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14091593 |
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12530287 |
Nov 25, 2009 |
8198445 |
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PCT/JP08/52779 |
Feb 19, 2008 |
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13458400 |
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Current U.S.
Class: |
540/450 ;
540/542; 544/157; 546/22; 548/402; 548/413; 564/15 |
Current CPC
Class: |
C07C 2601/12 20170501;
B01J 31/1815 20130101; C07C 2601/08 20170501; C07D 333/16 20130101;
C07C 29/40 20130101; C07F 9/28 20130101; C07C 29/40 20130101; C07C
2602/10 20170501; C07C 2601/14 20170501; C07F 9/36 20130101; C07F
9/6533 20130101; C07F 9/572 20130101; C07F 9/5532 20130101; B01J
2231/643 20130101; C07F 9/59 20130101; B01J 2531/26 20130101; C07C
29/40 20130101; C07C 29/40 20130101; C07B 53/00 20130101; C07C
2602/12 20170501; C07C 2602/08 20170501; C07C 29/40 20130101; C07C
2601/10 20170501; C07C 41/30 20130101; C07B 2200/07 20130101; C07F
19/00 20130101; C07C 41/30 20130101; C07C 33/34 20130101; C07C
33/46 20130101; C07C 33/16 20130101; C07C 33/20 20130101; C07C
43/23 20130101 |
Class at
Publication: |
540/450 ;
548/413; 546/22; 544/157; 540/542; 548/402; 564/15 |
International
Class: |
C07F 19/00 20060101
C07F019/00; C07F 9/28 20060101 C07F009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 9, 2007 |
JP |
2007-061030 |
Claims
1. A ligand which is a phosphoramide compound represented by
general formula (8a), (8b), (9a) or (9b): ##STR00043## wherein
R.sup.1 is a monovalent hydrocarbon group which is selected from
the group consisting of an alkyl group, an alkenyl group, an
alkynyl group, an aryl group, an arylalkyl group and an arylalkenyl
group, and which may have at least one substituent; R.sup.2 and
R.sup.3 independently are monovalent hydrocarbon groups which are
selected from the group consisting of an alkyl group, an alkenyl
group, an alkynyl group, an aryl group, an arylalkyl group and an
arylalkenyl group, which may have at least one substituent, and
which are each bound to a phosphorus atom directly or via an atom
other than carbon atom; R.sup.6 is a hydrogen atom or a monovalent
hydrocarbon group which is selected from the group consisting of an
alkyl group, an alkenyl group, an alkynyl group, an aryl group, an
arylalkyl group and an arylalkenyl group, and which may have at
least one substituent; R.sup.7 is a monovalent hydrocarbon group
which is selected from the group consisting of an alkyl group, an
alkenyl group, an alkynyl group, an aryl group, an arylalkyl group
and an arylalkenyl group, and which may have at least one
substituent; X is an oxygen atom or sulfur atom; and B is a
methylene group or carbonyl group when the ligand is represented by
the general formula (8a) or (8b), and B is a carbonyl group when
the ligand is represented by the general formula (9a) or (9b).
2. The ligand according to claim 1, which is represented by the
general formula (8a).
3. The ligand according to claim 1, which is represented by the
general formula (8b).
4. The ligand according to claim 1, which is represented by the
general formula (9a).
5. The ligand according to claim 1, which is represented by the
general formula (9b).
6. A complex comprising: and according to claim 1; and a central
metal comprising zinc atom.
7. The complex according to claim 6, which is represented by
general formula (10): L.sub.mZnR.sup.8(ZnR.sup.8R.sup.9).sub.n (10)
wherein L is said ligand or a compound obtained from said ligand in
which the hydrogen atom on the nitrogen atom is eliminated; R.sup.8
and R.sup.9 independently are monovalent hydrocarbon groups which
may have at least one substituent; m is an integer of 1 to 10; and
n is an integer of 0 to 10.
8. The complex according to claim 6, wherein an organozinc compound
represented by ZnR.sup.8R.sup.9 is coordinated to said ligand,
wherein R.sup.8 and R.sup.9 independently are monovalent
hydrocarbon groups which are selected from the group consisting of
an alkyl group, an alkenyl group, an alkynyl group, an aryl group,
an arylalkyl group and an arylalkenyl group, and which may have at
least one substituent.
9. A catalyst comprising the complex according to claim 6.
10. The catalyst according to claim 9, which is capable of
catalyzing a synthesis of an optically active alcohol.
11. The catalyst according to claim 10, wherein the optically
active alcohol is an optically active tertiary alcohol.
12. The phosphoramide compound according to claim 1, wherein
R.sup.6 is a hydrogen atom, an alkyl group or an arylalkyl group,
and R.sup.7 is an aryl group, an arylalkyl group or an arylalkenyl
group, and R.sup.6 and R.sup.7 are not substituted with an oxygen
atom, a nitrogen atom or a sulfur atom.
13. The ligand according to claim 2, wherein X is a sulfur
atom.
14. The ligand according to claim 2, wherein B is a methylene
group.
15. The ligand according to claim 3, wherein X is a sulfur
atom.
16. The ligand according to claim 3, wherein B is a methylene
group.
17. The ligand according to claim 4, wherein X is a sulfur
atom.
18. The ligand according to claim 4, wherein X is an oxygen
atom.
19. The ligand according to claim 5, wherein X is a sulfur
atom.
20. The ligand according to claim 5, wherein X is an oxygen atom.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
13/458,400, filed Apr. 27, 2012, the entire content of which is
incorporated by reference herein. U.S. Ser. No. 13/458,400 is a
divisional of U.S. Ser. No. 12/530,287, filed Sep. 8, 2009, which
is the national stage of PCT/JP08/052779, filed Feb. 19, 2008, and
claims the benefits of priority to Japanese Application No.
2007-061030, filed Mar. 9, 2007.
TECHNICAL FIELD
[0002] The present invention relates to a novel phosphoramide
compound and a method for producing the same. Additionally, the
present invention relates to a ligand composed of the phosphoramide
compound, a complex comprising the ligand, and a catalyst
comprising the complex. Further, the present invention relates to a
method for producing an optically active alcohol using the
above-mentioned phosphoramide compound or the like.
DESCRIPTION OF THE RELATED ART
[0003] As an alcohol synthesis method, an alkyl addition reaction
is known in which a carbonyl compound such as an aldehyde compound
and a ketone compound is reacted with an organometal nucleophilic
agent.
[0004] Many of biologically active substances are optically active
substances having an asymmetric carbon atom. It is therefore
important to obtain an optically active substance that has a
desired absolute configuration. For example, optically active
substances can be obtained in such a manner that a racemic mixture
is synthesized, and then an optically active substance is isolated
by optical resolution etc. However, this method requires a chemical
alteration and thus is inefficient. For this reason, asymmetric
synthesis methods by which optically active substances can be
obtained selectively have long been under development. For example,
the following methods are known as the method for obtaining
optically active alcohols by reaction of a carbonyl compound with
an organometal nucleophilic agent.
[0005] An asymmetric phenylation reaction for obtaining an
optically active tertiary alcohol is disclosed in Non-Patent
document 1. It is described that the enantiomeric excess (ee) of
the product is 91% ee in Non-Patent document 1.
##STR00002##
[0006] Methods for obtaining an optically active tertiary alcohol
by adding a sulfonamide compound having a specific structure, and
reacting a ketone with diethylzinc using Ti(Oi-Pr).sub.4 as a
reactant are disclosed in Non-Patent Documents 2 to 5. One example
thereof is as follows. Non-Patent Documents 2 to 5 disclose that
the enantiomeric excess (ee) of the product is up to 99% ee.
##STR00003##
[0007] Non-Patent Document 6 discloses a method for obtaining an
optically active tertiary alcohol by an asymmetric alkynylation
reaction of aromatic and aliphatic ketones.
##STR00004##
[0008] Additionally, a method for producing an optically active
alcohol by adding a dialkylzinc to an aldehyde is disclosed in
Patent Document 1. It is described that an asymmetric catalyst
having a phosphine oxide unit or phosphine sulfide unit at the 3-
and 3'-positions of the binaphthol skeleton is used in Patent
Document 1.
[0009] [Non-Patent Document 1] J. Am. Chem. Soc., 1998, 120,
445-446
[0010] [Non-Patent Document 2] J. Am. Chem. Soc., 2002, 124,
10970-10971
[0011] [Non-Patent Document 3] J. Org. Lett., 2003, 5,
3641-3644
[0012] [Non-Patent Document 4] J. Am. Chem. Soc., 2005, 127,
16416-16425
[0013] [Non-Patent Document 5] J. Org. Chem., 2005, 70, 448-455
[0014] [Non-Patent Document 6] Angew. Chem. Int. Ed. 2003, 42,
2895-2898
[0015] [Patent Document 1] Japanese Patent Laid-Open Application
Publication No. JP-A 2006-35125
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0016] An optically active alcohol is an important compound as a
synthetic intermediate for drugs and the like. Hence, a method of
synthesizing an optically active alcohol by an alkyl addition
reaction in which a carbonyl compound is reacted with an
organometal nucleophilic agent has been required.
[0017] Particularly, the synthesis of a tertiary alcohol is limited
to alkyl addition reaction of a ketone using an organometal
nucleophilic agent. Additionally, the alkyl addition reaction is
accompanied by side reactions, as described below, such as a
reduction reaction and an aldol reaction. It is thus difficult to
obtain only the desired tertiary alcohol in sufficient yield.
Moreover, the enantioselective production of an optically active
tertiary alcohol using an asymmetric catalyst is considered
extremely difficult.
##STR00005##
[0018] When viewed globally, only the research groups as described
in Non-Patent Documents 1 to 6 have been successful in catalystic
asymmetric synthesis of tertiary alcohols. However, these methods
are inferior in practicality; the type of applicable alkylating
agents is limited, and a large amount of titanium additive is
required for the reaction.
[0019] An object of the present invention is to provide a method
for obtaining an optically active alcohol using a carbonyl compound
with a higher efficiency and higher enantioselectivity than before.
Another object of the present invention is to provide a catalyst, a
ligand and a novel phosphoramide compound constituting the ligand,
that lead to an optically active alcohol with a higher efficiency
and higher enantioselectivity than before, and a method for
producing such a phosphoramide compound.
Means For Solving Problems
[0020] The phosphoramide compound of the present invention is
characterized by being represented by the following general formula
(1) or (1').
##STR00006##
(In the formula, R.sup.1 to R.sup.5 are each independently
monovalent hydrocarbon groups, R.sup.2 and R.sup.3 are each bound
to a phosphorus atom directly or via an atom other than carbon
atom, R.sup.2 and R.sup.3 may be bonded to each other to form a
ring, and R.sup.4 and R.sup.5 may be bonded to each other to form a
ring, X is an oxygen atom or sulfur atom, and B is a methylene
group or carbonyl group.)
[0021] The method for producing the phosphoramide compound of the
present invention is characterized by comprising the steps of:
[0022] (A) protecting the amino group of a compound represented by
the following general formula (2a) or (2b) with a protective group
to form a compound represented by the following general formula
(3a) or (3b);
[0023] (B) reacting the compound represented by the general formula
(3a) or (3b) with an amine compound to form an amide compound
represented by the following general formula (4a) or (4b);
[0024] (C) deprotecting the protective group of the amine compound
represented by the general formula (4a) or (4b), or deprotecting
the protective group of the amine compound represented by the
general formula (4a) or (4b) and reducing the amide group of the
amide compound represented by the general formula (4a) or (4b), to
form a compound represented by the following general formula (5a)
or (5b); and
[0025] (D) reacting the compound represented by the general formula
(5a) or (5b) with a phosphorus compound represented by the
following general formula (6) to form a phosphoramide compound of
the present invention.
##STR00007##
(In the formulae, R.sup.1 to R.sup.5 are each independently
monovalent hydrocarbon groups, R.sup.2 and R.sup.3 are each bound
to a phosphorus atom directly or via an atom other than carbon
atom, R.sup.2 and R.sup.3 may be bound to each other to form a
ring, R.sup.4 and R.sup.5 may also be bound to each other to form a
ring, X is an oxygen atom or sulfur atom, Y is a halogen atom, A is
a protective group, and B is a methylene group or carbonyl
group.)
[0026] The ligand of the first embodiment according to the present
invention is characterized in that it is the phosphoramide compound
of the present invention. Additionally, the ligand of the second
embodiment according to the present invention is characterized by
represented by the following formula (8a), (8b), (9a) or (9b).
##STR00008##
(In the formula, R.sup.1 to R.sup.3 and R.sup.7 are each
independently monovalent hydrocarbon groups, R.sup.2 and R.sup.3
are each bound to a phosphorus atom directly or via an atom other
than carbon atom, R.sup.6 is a hydrogen atom or a monovalent
hydrocarbon group, X is an oxygen atom or sulfur atom, and B is a
methylene group or carbonyl group.)
[0027] The complex of the present invention is characterized in
that a central metal is zinc atom, and a ligand is the ligand of
the present invention. Additionally, the catalyst of the present
invention is characterized by comprising the complex of the present
invention.
[0028] The method for producing an optically active alcohol of the
first embodiment according to the present invention is
characterized in that the phosphoramide compound of the present
invention or the ligand of the present invention is added to react
a carbonyl compound with an organozinc compound represented by the
following general formula (11) or with organozinc compounds
represented by the following general formulae (12) and (13).
ZnR.sup.10R.sup.11 (11)
ZnR.sup.12R.sup.13 (12)
ZnR.sup.14R.sup.15 (13)
(In the formulae, R.sup.10 and R.sup.11 are each independently
monovalent hydrocarbon groups, and at least one of them is an alkyl
group, alkenyl group or alkynyl group, R.sup.12 and R.sup.13 are
each independently aryl group, arylalkyl group or arylalkenyl
group, and R.sup.14 and R.sup.15 are each independently alkyl
group, alkenyl group or alkynyl group.)
[0029] The method for producing an optically active alcohol of the
second embodiment according to the present invention is
characterized in that a carbonyl compound is subjected to reaction
with an organozinc compound represented by the following general
formula (11) or with organozinc compounds represented by the
following general formulae (12) and (13) in the presence of the
complex of the present invention or the catalyst of the present
invention.
ZnR.sup.10R.sup.11 (11)
ZnR.sup.12R.sup.13 (12)
ZnR.sup.14R.sup.15 (13)
(In the formulae, R.sup.10 and R.sup.11 are each independently
monovalent hydrocarbon groups, and at least one of them is an alkyl
group, alkenyl group or alkynyl group, R.sup.12 and R.sup.13 are
each independently aryl group, arylalkyl group or arylalkenyl
group, and R.sup.14 and R.sup.15 are each independently alkyl
group, alkenyl group or alkynyl group.)
[Effects of the Invention]
[0030] According to the present invention, an alkyl addition
reaction in which a carbonyl compound such as an aldehyde and a
ketone is reacted with an organometal nucleophilic agent can be
performed using a novel phosphoramide compound as a ligand. As a
result, an optically active alcohol can be synthesized with a
higher efficiency and higher enantioselectivity than before. When
the optically active alcohol synthesized by the present invention
is used as a synthetic intermediate for drugs or pesticides (e.g.,
synthetic intermediates for clemastine that is often used as an
antihistamine), the target drugs or pesticides can be produced with
a high efficiency.
BEST MODE FOR CARRYING OUT THE INVENTION
(1) Phosphoramide Compound and Method For Producing the Same
[0031] The phosphoramide compound of the present invention is
characterized by being represented by the above-described general
formula (1) or (1').
[0032] In the general formulae (1) and (1'), R.sup.1 to R.sup.5 are
each independently monovalent hydrocarbon groups. Examples of the
monovalent hydrocarbon group include an alkyl group, an alkenyl
group, an alkynyl group, an aryl group, an arylalkyl group and an
arylalkenyl group.
[0033] The number of carbon atoms in the alkyl, alkenyl and alkynyl
groups (hereinafter generically referred to as "alkyl group etc.")
is not particularly limited. The number of carbon atoms in the
above-mentioned alkyl group is usually 1 to 12, preferably 1 to 10,
more preferably 1 to 8, further preferably 1 to 6, and particularly
1 to 4. Moreover, the number of carbon atoms in the above-mentioned
alkenyl and alkynyl groups is usually 2 to 12, preferably 2 to 10,
more preferably 2 to 8, further preferably 2 to 6, and particularly
2 to 4. When the alkyl group etc. have a cyclic structure, the
number of carbon atoms in each of the alkyl group etc. is usually 4
to 12, preferably 4 to 10, more preferably 5 to 8, and further
preferably 6 to 8.
[0034] The structure of the alkyl group etc. is not particularly
limited. The alkyl group etc. may have a straight or branched chain
structure. The alkyl group etc. may have a chain or cyclic
structure (cycloalkyl, cycloalkenyl, and cycloalkynyl groups).
Additionally, the alkyl group etc. may have one or more types of
other substituents. Furthermore, the alkyl group etc. may contain
one or more atoms other than carbon atom and hydrogen atom. For
example, the alkyl group etc. may have, as a substituent, a
substituent containing atoms other than carbon atom and hydrogen
atom. Moreover, the alkyl group etc. may include one or more atoms
other than carbon atom and hydrogen atom in the chain or cyclic
structure. Example of the atom other than carbon atom and hydrogen
atom include at least one of oxygen atom, nitrogen atom and sulfur
atom.
[0035] Examples of the above-mentioned alkyl group include methyl
group, ethyl group, n-propyl group, i-propyl group, n-butyl group,
i-butyl group, sec-butyl group, t-butyl group, pentyl group,
isopentyl group, neopentyl group, hexyl group, heptyl group, octyl
group and 2-ethylhexyl group. Examples of the above-mentioned
cycloalkyl group include cyclopentyl group, cyclohexyl group,
cycloheptyl group and 2-methylcyclohexyl group. Examples of the
above-mentioned alkenyl group include vinyl group, allyl group and
isopropenyl group. Examples of the above-mentioned cycloalkenyl
group include cyclohexenyl group.
[0036] The number of carbon atoms in the aryl, arylalkyl and
arylalkenyl groups (hereinafter generically referred to as "aryl
group etc.") is not particularly limited. The number of the aryl
group etc. is usually 6 to 15, preferably 6 to 12, and more
preferably 6 to 10.
[0037] The structure of the aryl group etc. is not particularly
limited. The aryl group etc. may have one or more types of other
substituents. For example, the aromatic ring contained in the aryl
group etc. may have one or more types of other substituents. The
position of the substituent may be any of o-, m-, and p- positions.
Specific examples of the substituent include at least one of a
halogen atom, an alkyl group, an alkenyl group, a nitro group, an
amino group, a hydroxy group and an alkoxy group. When the
substituent is located on the aromatic ring, the position of the
substituent may be any of o-, m-, and p-positions.
[0038] The above-mentioned halogen atom may be at least one of a
fluorine atom, a chlorine atom and a bromine atom.
[0039] Examples of the above-mentioned alkyl and alkenyl groups
include at least one of an alkyl group and an alkenyl group, having
1 to 6 carbon atoms, and preferably 1 to 4 carbon atoms. Specific
examples of the above-mentioned alkyl and alkenyl groups include at
least one of methyl group, ethyl group, n-propyl group, i-propyl
group, i-butyl group, sec-butyl group and t-butyl group. In
addition, the above-mentioned alkyl and alkenyl groups may further
have other substituents, and may be a halogenated alkyl and
halogenated alkenyl groups. For example, the alkyl group may be
exemplified as a group in which a part or all of hydrogen atoms in
methyl or ethyl group are substituted with a halogen atom (at least
one of a fluorine atom, a chlorine atom and a bromine atom) such as
CF.sub.3--, CCl.sub.3-- or the like.
[0040] Examples of the above-mentioned alkoxy group include an
alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon
atoms, and more preferably 1 to 3 carbon atoms. Specific examples
of the above-mentioned alkoxy group include methoxy group, ethoxy
group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy
group, sec-butoxy group and t-butoxy group.
[0041] The aromatic ring contained in the aryl group etc. may have
one or more types of a hetero atom such as oxygen atom, nitrogen
atom, and sulfur atom. That is, the aromatic ring contained in the
aryl group etc. may be an aromatic heterocycle (furan, thiophene,
pyrrole, benzofuran, indole, thiophene, pyrazole, imidazole,
triazole, isoxazole, oxazole, isothiazole, thiazole, pyridine,
quinoline, isoquinoline, pyrimidine, and the like).
[0042] Specific examples of the above-mentioned aryl group include
phenyl group, tolyl group, ethylphenyl group, xylyl group, cumenyl
group, mesityl group, methoxyphenyl group (o-, m-, and p-),
ethoxyphenyl group (o-, m-, and p-), 1-naphthyl group, 2-naphthyl
group, biphenylyl group and the like. Specific examples of the
above-mentioned arylalkyl group include benzyl group, methoxybenzyl
group (o-, m-, and p-), ethoxybenzyl group (o-, m-, and p-), and
phenethyl group. Specific examples of the above-mentioned
arylalkenyl group include styryl group and cinnamyl group.
[0043] R.sup.2 and R.sup.3 are each directly bound to a phosphorus
atom or are bound to the phosphorus atom via an atom other than
carbon atom (hereinafter this binding is referred to as "indirect
binding"). Examples of the atom other than carbon atom include an
oxygen atom, a nitrogen atom and a sulfur atom. Specific examples
of the indirect binding include a structure "R.sup.2 (or
R.sup.3)--O--P" and a structure "R.sup.2 (or R.sup.3)--N(E)-P". Of
course, both R.sup.2 R.sup.3 may be bound to the phosphorus atom
directly or indirectly, or one of R.sup.2 and R.sup.3 may be
directly bound to the phosphorus atom, and the other may be
indirectly bound to the phosphorus atom. When R.sup.2 and R.sup.3
are bound to the phosphorus atom indirectly (e.g., via an oxygen
atom), specific R.sup.2 and R.sup.3 can each independently be
monovalent hydrocarbon groups having 3 or more carbon atoms,
preferably 4 or more carbon atoms, and more preferably 4 to 10
carbon atoms.
[0044] When the atom other than carbon atom is a nitrogen atom, E
bound to the nitrogen atom may be a hydrogen atom or other
monovalent hydrocarbon group. The other monovalent hydrocarbon
group may be the same as or different from R.sup.2 (or R.sup.3).
Further, R.sup.2 (or R.sup.3) and the other monovalent hydrocarbon
group may be bound to each other to form a ring. The explanation of
R.sup.1 to R.sup.3 of the phosphoramide compound of the present
invention is applicable to the structure and contents of the other
monovalent hydrocarbon group. When two monovalent hydrocarbon
groups are bonded to the above nitrogen atom in the present
invention, at least one of them may correspond to R.sup.2 (or
R.sup.3). Examples of the other monovalent hydrocarbon group
include an alkyl group, alkenyl group and alkynyl group, having 1
to 5 carbon atoms. Specific examples of the other monovalent
hydrocarbon group include methyl group, ethyl group, n-propyl group
and i-propyl group. Specific examples of the above-mentioned
structure "R.sup.2 (or R.sup.3)--N(E)-P" include a structure
"(CH.sub.3).sub.2N--P--" and a structure
"(CH.sub.3CH.sub.2).sub.2N--P--".
[0045] R.sup.2 and R.sup.3 may be bound to each other to form a
ring. R.sup.4 and R.sup.5 may also be bound to each other to form a
ring. When R.sup.2 and R.sup.3 are bound to each other to form a
ring, and R.sup.4 and R.sup.5 are bound to each other to form a
ring, the structure of such rings is not particularly limited. For
example, the number of ring members is not particularly limited.
When R.sup.2 and r.sup.3 are bound to each other to form a ring,
the number of ring members may be four to ten, and preferably five
to eight, including the phosphorus atom to which R.sup.2 and
R.sup.3 are bound. When R.sup.4 and R.sup.5 are bound to each other
to form a ring, the number of ring members may be four to ten, and
preferably five to eight, including the nitrogen atom to which
R.sup.4 and r.sup.5 are bound. The ring may contain a hetero atom
such as an oxygen atom, a nitrogen atom and a sulfur atom in its
structure. In addition, the ring may have other substituent.
Further, the ring may have an unsaturated bond in its
structure.
[0046] Specific examples of the ring formed by binding of R.sup.2
and R.sup.3 are shown below.
##STR00009##
(In the above formulae, D is a hetero atom such as an oxygen atom,
a nitrogen atom and a sulfur atom.)
[0047] Specific examples of the ring formed by binding of R.sup.4
and R.sup.5 are shown below. Specific examples of the ring include
a five-membered ring structure formed by tetramethylene group, a
six-membered ring structure formed by pentamethylene group, a
seven-membered ring structure formed by hexamethylene group, and a
eight-membered ring structure formed by heptamethylene group. In
addition, examples of the structure containing a hetero atom in the
ring structure include a structure containing an oxygen atom (a
morpholyl group).
##STR00010##
[0048] R.sup.1 to R.sup.5 may be all the same groups or may be
partly or completely different groups. For example, R.sup.2 may be
the same as or different from R.sup.3. Additionally, R.sup.1 to
R.sup.3 may be all the same groups. Among R.sup.1 to R.sup.3,
R.sup.2 and R.sup.3 may be the same groups, and R.sup.1 may be
different from these groups. R.sup.4 may be the same as or
different from R.sup.5.
[0049] Specific structures of R.sup.1 to R.sup.5 are not
particularly limited. As the structures of R.sup.1 to R.sup.5, each
structure described above can be adopted in a suitable combination,
if necessary.
[0050] R.sup.1 may be an alkyl group, an arylalkyl group or an
arylalkenyl group. The alkyl group may be an alkyl group explained
above, particularly methyl group, ethyl group, n-propyl group,
i-propyl group, n-butyl group, sec-butyl group or t-butyl group.
The arylalkyl group may be an arylalkyl group explained above,
particularly benzyl group, or o-, m-, and p-alkoxybenzyl groups
such as methoxybenzyl group and ethoxybenzyl group. In addition,
R.sup.1 can be an alkyl group, an aryl group, an arylalkyl group or
an arylalkenyl group and be one which is different from either or
both of R.sup.2 and R.sup.3. When R.sup.2 and R.sup.3 are the
above-mentioned alkyl groups etc. (for example, an alkyl group
having 5 or more carbon atoms, 3 or less carbon atoms, or 2 or less
carbon atoms), R.sup.1 can be an aryl group, an arylalkyl group or
an arylalkenyl group.
[0051] R.sup.2 and R.sup.3 may be same or different cycloalkyl
group, aryl group, arylalkyl group or arylalkenyl group. The aryl
group may be an aryl group explained above, particularly phenyl
group, 1-naphthyl group, 2-naphthyl group, o-, m- and
p-alkoxyphenyl groups such as methoxyphenyl group and ethoxyphenyl
group, or an o-, m- and p-halogenated alkylphenyl group such as
trifluoromethylphenyl group and trichloromethylphenyl group. The
arylalkyl group may be an arylalkyl group explained above,
particularly benzyl group, or o-, m-, and p-alkoxybenzyl groups
such as methoxybenzyl group and ethoxybenzyl group. In addition,
when R.sup.1 is the above-mentioned alkyl groups etc., at least one
of R.sup.2 and R.sup.3 may be a cycloalkyl group, an aryl group, an
arylalkyl group or an arylalkenyl group.
[0052] In the general formula (1) or (1') described above, X is an
oxygen atom or sulfur atom. X is usually an oxygen atom.
[0053] Examples of the phosphoramide compound of the present
invention include compounds represented by the following general
formulae.
##STR00011##
[0054] In the above formulae, X is an oxygen atom or sulfur atom. B
is a methylene group or carbonyl group. R.sup.1' is an alkyl group
or arylalkyl group having 2 or more carbon atoms, preferably 3 or
more carbon atoms, and more preferably 3 to 10 carbon atoms, which
is different from R.sup.2' and R.sup.3'. R.sup.2' and R.sup.3' are
same or different cycloalkyl group, aryl group, arylalkyl group or
aryl alkenyl group. R.sup.4' is an alkyl group, alkenyl group or
alkynyl group. The explanation of R.sup.1 to R.sup.4 is applicable
to R.sup.1' to R.sup.4'.
[0055] Specific examples of the phosphoramide compound of the
present invention include the following compounds. The
configuration of the group corresponding to R.sup.1 may be reversed
in these compounds. "Cy" in the following formula is a cycloalkyl
group (a cyclohexyl group and the like).
##STR00012##
[0056] The method for producing the phosphoramide compound of the
present invention is not particularly limited. The phosphoramide
compound of the present invention can be produced by the method for
producing the phosphoramide compound of the present invention.
(2) Method For Producing Phosphoramide Compound
[0057] The method for producing the phosphoramide compound of the
present invention comprises Steps (A) to (D), as described above.
In the method for producing the phosphoramide compound of the
present invention, the explanation of R.sup.1 to R.sup.5 and X in
the phosphoramide compound of the present invention is
applicable.
<Step (A)>
[0058] The step (A) is a step to protect the amino group of the
compound represented by the general formula (2a) or (2b) described
above (hereinafter referred to as "compound (2a) or (2b)"), with a
protective group to form the compound represented by the general
formula (3a) or (3b) described above (hereinafter referred to as
"compound (3a) or (3b)").
[0059] Commercially available amino acids (natural and non-natural
amino acids) can be used as the compound (2a) or (2b), which is a
starting material. Of course, the compound (2a) and (2b) may be
ones synthesized by any method. Additionally, the starting material
may consist only of an optically active substance of the compound
(2a) or (2b), or may be a mixture of an optically active substance
such as a racemic modification. When the starting material is a
mixture of an optically active substance such as racemic
modification, an optically active phosphoramide compound can be
obtained by optical resolution after the reaction. The process for
the optical resolution is not particularly limited, and known
processes are applicable. In the production method of the present
invention, the optically active substances of the compound (2a) and
(2b) are preferably used as the starting material because an
optically active phosphoramide compound can be obtained without an
optical resolution.
[0060] A in the above formula is a protective group. The structure
of the protective group is not particularly limited so long as it
can protect the amino group contained in the compound (2a) or (2b).
Examples of the protective group include t-butoxycarbonyl group
(Boc), benzyloxycarbonyl group, and t-amyloxycarbonyl group. For
example, the above-described t-butoxycarbonyl group, which is a
protective group, can be introduced into the amino group by
reaction of the compound (2a) or (2b) with di-t-butyl
carbonate.
[0061] The reaction conditions for the step (A) are also not
particularly limited. The step (A) can be carried out by reacting,
in a solvent such as ethanol, the compound (2a) or (2b) with a
protecting reagent for introducing the above-mentioned protective
group. The reaction is preferably carried out at room temperature
(20.degree. C.-30.degree. C.), although the reaction temperature is
not particularly limited.
<Step (B)>
[0062] The step (B) is a step to react the compound (3a) or (3b)
with an amine compound to form the amide compound represented by
the general formula (4a) or (4b) described above (hereinafter
referred to as "amide compound (4a) or (4b)").
[0063] In the step (B), the type of the amine compound is not
particularly limited so long as the amide compound (4a) or (4b) can
be obtained. A secondary amine having R.sup.4 and R.sup.5 is
usually used. In the step (B), an amide compound may be obtained
using a primary amine having R.sup.4 (or R.sup.5), and then R.sup.5
(or R.sup.4) may be introduced by N-alkylation reaction, thereby
forming the amide compound (4a) or (4b). In addition, the amine
compound may be a cyclic amine compound or an acyclic amine
compound. An amine compound having four to ten -membered ring and
preferably five to eight -membered ring can be used as the cyclic
amine compound. The ring may contain a hetero atom such as an
oxygen atom, a nitrogen atom and a sulfur atom in its structure.
Further, the ring may have other substituents. Moreover, the ring
may have an unsaturated bond in its structure. Specific examples of
the cyclic amine compound include pyrrolidine, piperidine and
morpholine.
[0064] The reaction conditions for the step (B) are not
particularly limited so long as the amide compound (4a) or (4b) can
be obtained. An alkyl halide such as dichloromethylene can be used
as a solvent. The reaction is preferably performed at room
temperature (20.degree. C.-30.degree. C.), although the reaction
temperature is not particularly limited. The reaction time is
usually in the range from 1 to 48 hours, preferably from 3 to 30
hours, and more preferably from 12 to 24 hours. Additionally,
dicyclocarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) and the
like can be added.
[0065] Further, the proportions of the compound (3a) or (3b) and
the amine compound are not also particularly limited in the
producing method of the present invention. Generally, 1 to 3
equivalents, and preferably 1.5 to 2.5 equivalents of the amine
compound can be used per equivalent of the compound (3a) or (3b).
Moreover, the proportions of DCC and other components are not also
particularly limited in the producing method of the present
invention. For example, 1 to 2 equivalents of each of DCC and HOBt
can be used per equivalent of the compound (3a) or (3b) in the
producing method of the present invention.
<Step (C)>
[0066] The step (C) is a step to deprotect the protective group of
the amide compound (4a) or (4b) (hereinafter referred to as "step
(C1)"), or deprotect the protective group of the amide compound
(4a) or (4b) while reducing the amide group of the amide compound
(4a) or (4b) (hereinafter referred to as "step (C2)"), to form the
compound represented by the general formula (5a) or (5b) described
above (hereinafter referred to as "compound (5a) or (5b)").
[0067] In the present invention, a compound wherein B is a carbonyl
group can be formed by the step (C1). Additionally, a compound
wherein B is a methylene group can be formed by the step (C2) in
the present invention.
[0068] The deprotection method and its reaction conditions are not
particularly limited in the step (C). The deprotection method and
its reaction conditions can be suitably selected according to the
type of the protective group. When the protective group is, for
example, a t-butoxycarbonyl group, the protective group can be
deprotected by an acid treatment using AcOH, AcCl, HBr or the
like.
[0069] The method for the reduction of the amide group and its
reaction conditions are not particularly limited in the step (C).
Example of the method for the reduction of the amide group includes
a method in which an amide group is reduced with lithium aluminum
hydride (LiAlH.sub.4) in a solvent of tetrahydrofuran or ether. In
this case, the amount of LiA1H.sub.4 is usually in the range from 1
to 10 equivalents, preferably from 2 to 8 equivalents, and more
preferably from 3 to 7 equivalents.
[0070] In the step (C2), the order of the "reduction of the amide
group" and "deprotection of the protective group" is not
particularly limited. The "deprotection of the protective group"
may be performed after performing the "reduction of the amide
group" in the present invention. Alternatively, the "reduction of
the amide group" can be performed after performing the
"deprotection of the protective group" in the present
invention.
<Step (D)>
[0071] The step (D) is a step in which the compound (5a) or (5b) is
reacted with the phosphorus compound represented by the formula (6)
described above (hereinafter referred to as "phosphorus compound
(6)") to form a phosphoramide compound of the present
invention.
[0072] The explanation of R.sup.2, R.sup.3 and X in the
phosphoramide compound of the present invention is applicable to
R.sup.2, R.sup.3 and X in the above formula (6). Moreover, Y in the
formula (6) is a halogen atom. Examples of the halogen atom include
fluorine atom, chlorine atom and bromine atom.
[0073] The amount of the phosphorus compound (6) to be used is not
particularly limited in the step (D). The amount of the phosphorus
compound (6) is usually in the range from 1 to 3 equivalents,
preferably from 1 to 2 equivalents, and more preferably from 1 to
1.5 equivalents based on 1 equivalent of the compound (5a) or
(5b).
[0074] An amine compound can further be coexistent in the step (D).
Coexistence of the amine compound can improve the reaction
efficiency of the compound (5a) or (5b) with the phosphorus
compounds (6). Examples of the amine compound include triethyl
amine and the like. The amount of the amine compound is usually in
the range from 1 to 4 equivalents, preferably from 1 to 3
equivalents, and more preferably from 1 to 2.5 equivalents per
equivalent of the compound (5a) or (5b).
[0075] The reaction conditions of the step (D) are not particularly
limited. The reaction temperature may be room temperature
(20.degree. C.-30.degree. C.). The reaction time may be in the
range from 1 to 24 hours, and is preferably from 1 to 12 hours,
more preferably from 1 to 6 hours.
<Others>
[0076] The phosphoramide compound of the present invention
represented by the above formula (1) or (1') wherein X is an oxygen
atom can be obtained by reaction with a halogenated phosphine oxide
having R.sup.2 and R.sup.3. Further, the phosphoramide compound of
the present invention represented by the above formula (1) or (1')
wherein X is a sulfur atom can be obtained by reaction with a
halogenated phosphine sulfide having R.sup.2 and R.sup.3.
[0077] Each step in the production method of the present invention
may be carried out after isolation of each product, or may be
carried out in a series without isolation of the product.
[0078] The production method of the present invention may include
steps other than the above-described steps. For example, the other
steps are exemplified as other chemical reaction steps. In
addition, the production method of the present invention may
optionally comprise, as other steps, optical resolution step for
separating only optically active substances, and physical operation
steps including concentration, purification, isolation and the like
of the product.
(3) Ligand
[0079] The ligand of the first embodiment of the present invention
is expressed by the phosphoramide compound of the present
invention. In addition, the ligand of the second embodiment of the
present invention is expressed by the formula (8a), (8b), (9a) or
(9b), described above. The explanation of R.sup.1 to R.sup.3 and X
of the phosphoramide compound of the present invention is
applicable to R.sup.1 to R.sup.3 and X in the ligand of the second
embodiment of the present invention.
[0080] In the ligand of the second embodiment of the present
invention, R.sup.6 is a hydrogen atom or a monovalent hydrocarbon
group, and R.sup.7 is a monovalent hydrocarbon group. Examples of
the monovalent hydrocarbon group include an alkyl group, an alkenyl
group, an alkynyl group, an aryl group, an arylalkyl group and an
arylalkenyl group. The explanation of R.sup.1 to R.sup.3 in the
phosphoramide compound of the present invention is applicable to
the type and structure of the monovalent hydrocarbon group. B is a
methylene group or carbonyl group.
[0081] Specific structures of R.sup.1 to R.sup.3, and R.sup.7 are
not particularly limited. As the structures of R.sup.1 to R.sup.3,
R.sup.6, and R.sup.7, for example, each structure illustrated above
can be adopted in a suitable combination, if necessary. R.sup.6 and
R.sup.7 may be the same as or different from R.sup.1 to
R.sup.3.
[0082] Examples of the compounds represented by Formulae (8a),
(8b), (9a) and (9b) include those having the following
structures.
##STR00013##
[0083] In the above formulae, X is an oxygen atom or sulfur atom.
R.sup.1' is an alkyl group, aryl group or arylalkyl group, having
two or more carbon atoms, preferably three of more carbon atoms,
more preferably 3 to 10 which group is different from R.sup.2' and
R.sup.3'. R.sup.2' and R.sup.3' are same or different cycloalkyl
group, aryl group, arylalkyl group or arylalkenyl group. R.sup.6'
is an alkyl group (preferably an alkyl group having 1 to 5 carbon
atoms) or arylalkyl group. R.sup.7' is an aryl group, arylalkyl
group or arylalkenyl group. The explanation of R.sup.1 to R.sup.3
is applicable to R.sup.1' to R.sup.3'. The explanation of R.sup.6
and R.sup.7 is applicable to R.sup.6' and R.sup.7'.
(4) Complex
[0084] The complex of the present invention comprises zinc as the
central metal, and the ligand of the present invention as the
ligand.
[0085] The structure of the complex of the present invention is not
particularly limited so long as the central metal is zinc and the
ligand is that of the present invention. Specific example of the
complex of the present invention includes a complex in which an
organozinc compound represented by the general formula:
ZnR.sup.8R.sup.9 is coordinated to the ligand of the present
invention. Examples of the complex of the present invention include
a complex represented by the following general formula (10).
L.sub.mZnR.sup.8(ZnR.sup.8R.sup.9).sub.n (10)
[0086] R.sup.8 and R.sup.9 are each independently monovalent
hydrocarbon groups. Examples of the monovalent hydrocarbon group
include an alkyl group, an alkenyl group, an alkynyl group, an aryl
group, an arylalkyl group and an arylalkenyl group. The explanation
of R.sup.1 to R.sup.3 in the phosphoramide compound of the present
invention is applicable to the type and structure of the monovalent
hydrocarbon groups. R.sup.8 may be the same as or different from
R.sup.9.
[0087] L is a ligand of the present invention or a compound
obtained from the ligand in which the hydrogen atom on the nitrogen
atom is eliminated. That is, the complex of the present invention
may have a structure in which zinc is coordinated to the ligand of
the present invention. Alternatively, the complex of the present
invention may have a structure in which the hydrogen atom on the
nitrogen atom is eliminated from the ligand of the present
invention, and zinc is coordinated thereto (see the following
formula). When an organozinc compound is added to the ligand of the
present invention, gas generation may be observed. This is
presumably because the complex (C) of the present invention is
formed according to the following formula (note that this
explanation is the inventor's presumption; therefore, this
explanation and the following formulae are not intended to limit
the scope of the present invention).
##STR00014##
[0088] In the above formula, m is an integer in the range from 1 to
10, preferably from 1 to 8, more preferably from 1 to 5, further
preferably form 1 to 3, and particularly from 1 to 2. In addition,
n is an integer in the range from 0 to 10, preferably from 0 to 8,
more preferably from 0 to 5, further preferably from 0 to 3, and
particularly from 0 to 2. Usually, n is 1 or 0.
[0089] The complex of the present invention can be obtained by, for
example, mixing the ligand of the present invention and an
organozinc compound such as the organozinc compound represented by
ZnR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 are each independently
monovalent hydrocarbon groups, in a solvent such as an aliphatic
hydrocarbon including hexane, heptane and the like, an aromatic
hydrocarbon including toluene and the like, a halogenated alkyl
compound including methylene chloride. Additionally, an alkyne can
be mixed. In this case, it is considered that an alkynyl zinc
obtained by reaction of the added organozinc compound with the
alkyne is coordinated to the ligand of the present invention to
form the complex of the present invention (note that this
explanation is inventor's presumption; this explanation is not
intended to limit the scope of the present invention). That is, the
organic group contained in the added organozinc compound may be the
same as or different from the organic group bonded to zinc atom
that forms the complex of the present invention, for the complex of
the present invention.
[0090] The form of the complex of the present invention is not
particularly limited. The complex of the present invention may be
present in a solvent, or may be present as a residue after the
solvent is distilled off. Further, the complex of the present
invention may be used as-prepared. Moreover, the complex of the
invention may be, for example, formed in a reaction solvent without
being isolated as a complex, and may be continuously used in the
reaction.
(5) Catalyst
[0091] The catalyst of the present invention comprises the complex
of the present invention.
[0092] The composition of the catalyst of the present invention is
not particularly limited so long as the catalyst contains the
complex of the present invention. The catalyst of the present
invention may comprise components other than the complex of the
invention. The form of the catalyst of the present invention is not
particularly limited. The catalyst of the present invention may be
present in a solvent, or may be present as a residue after the
solvent is distilled off. Further, the catalyst of the invention
may be used as-prepared. Moreover, the catalyst of the invention
may be, for example, formed in a reaction solvent without being
isolated as a catalyst, and may be continuously used in the
reaction.
[0093] The catalyst can catalyze alkyl addition reaction in which a
carbonyl compound such as an aldehyde and a ketone is reacted with
an organometal nucleophilic agent. The catalyst can therefore be
used as a catalyst for alcohol synthesis. Moreover, the catalyst
exhibits excellent enantioselectivity. The catalyst can therefore
be used as a catalyst for the synthesis of an optically active
alcohol. In particular, the catalyst can be used as a catalyst for
the synthesis of an optically active tertiary alcohol by an alkyl
addition reaction of a ketone, which is conventionally difficult to
synthesize.
(6) Method For Producing Optically Active Alcohol
[0094] The method for producing optically active alcohol of the
first embodiment according to the present invention is
characterized in that the phosphoramide compound of the present
invention or the ligand of the present invention is added, and a
carbonyl compound such as an aldehyde compound and a ketone is
reacted with an organozinc compound represented by the general
formula (11) or with an organozinc compound represented by the
general formulae (12) and (13).
[0095] The method for producing optically active alcohol of the
second embodiment according to the present invention is
characterized in that a carbonyl compound such as an aldehyde
compound and a ketone is reacted with an organozinc compound
represented by the general formula (11) or with an organozinc
compound represented by the general formulae (12) and (13) in the
presence of the complex of the present invention or the catalyst of
the present invention.
[0096] There are differences between ketone and aldehyde when each
of them is used in an alcohol synthesis using an organozinc
compound. The differences are as follows. First, a ketone has a
lower reactivity rather than an aldehyde due to three-dimensional
and electronic factors. Secondary, the alcohol synthesis reaction
itself is often difficult to advance due to low reactivity of an
organozinc compound, and the reaction is sometimes accompanied by
side reactions. Third, the enantioface discrimination of a ketone
by a chiral catalyst is usually more difficult than the enantioface
discrimination of an aldehyde. The conventional asymmetric alkyl
addition reaction using a catalyst was therefore limited to the
synthesis of an optically active secondary alcohol using an
aldehyde. However, the method for producing an optically active
alcohol of the present invention can be applied to the production
of an optically active tertiary alcohol using a ketone compound, as
well as the synthesis of an optically active secondary alcohol
using an aldehyde compound. In particular, according to the alkyl
addition reaction of a ketone in the present invention, an
enantioselective optically active tertiary alcohol, which is
conventionally difficult to synthesize, can be synthesized with a
higher efficiency and high enantioselectivity than before. In the
following, "optically active alcohol" refers to "optically active
tertiary alcohol" when the starting material is a ketone compound,
and when the starting material is an aldehyde compound, it refers
to "optically active secondary alcohol".
[0097] The type and structure of the above-mentioned carbonyl
compound, which is a starting material, are not particularly
limited. The ketone compound may be an aromatic ketone or an
aliphatic ketone. In addition, the aldehyde compound may be an
aromatic aldehyde or an aliphatic aldehyde.
[0098] Examples of the ketone compound include ketone compounds
represented by the general formula (14) and (15).
##STR00015##
[0099] In the formula, R.sup.16 is a monovalent hydrocarbon group
having three or more carbon atoms. R.sup.17 is a different
monovalent hydrocarbon group from R.sup.16. Examples of the
monovalent hydrocarbon group include an alkyl group, an alkenyl
group, an alkynyl group, an aryl group, an arylalkyl group and an
arylalkenyl group. The explanation of R.sup.1 to R.sup.3 in the
phosphoramide compound of the present invention is applicable to
the types and structures of the alkyl group, alkenyl group, alkynyl
group, aryl group, arylalkyl group and arylalkenyl group. R.sup.17
in the general formula (14) can be a methyl group or an ethyl
group.
[0100] In the general formula (15), n is an integer of 2 or more,
preferably 2 to 6, and more preferably 2 to 5.
[0101] The aromatic ring in the general formula (15) may have one
or more substituents. The position of the substituent may be o-, m-
or p- positions. Examples of the substituent include at least one
of a halogen atom, an alkyl group, an alkenyl group, a nitro group,
an amino group, a hydroxy group and an alkoxy group. When a
substituent is located on the aromatic ring, the position of the
substituent may be o-, m- or p- positions.
[0102] The above-mentioned halogen atom may be at least one of a
fluorine atom, a chlorine atom and a bromine atom.
[0103] Examples of the above-mentioned alkyl and alkenyl groups
include at least one of alkyl group or alkenyl group having 1 to 6
carbon atoms, preferably 1 to 4 carbon atoms. Specific examples of
the above-mentioned alkyl and alkenyl groups include at least one
of methyl group, ethyl group, n-propyl group, i-propyl group,
i-butyl group, sec-butyl group and t-butyl group. In addition, the
above-mentioned alkyl and alkenyl groups may further have other
substituents, and may be a halogenated alkyl and halogenated
alkenyl groups. For example, the alkyl group may be exemplified as
a group in which a part or all of hydrogen atoms in methyl or ethyl
group are substituted with a halogen atom (at least one of a
fluorine atom, a chlorine atom and a bromine atom) such as
CF.sub.3--, CCl.sub.3--.
[0104] Examples of the above-mentioned alkoxy group include an
alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon
atoms, and more preferably 1 to 3 carbon atoms. Specific examples
of the above-mentioned alkoxy group include methoxy group, ethoxy
group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy
group, sec-butoxy group and t-butoxy group.
[0105] Examples of the above-mentioned aldehyde compound include an
aldehyde compound represented by the general formula: R.sup.18CHO.
In the formula, R.sup.18 is a monovalent hydrocarbon group.
Examples of the monovalent hydrocarbon group include an alkyl
group, an alkenyl group, an alkynyl group, an aryl group, an
arylalkyl group and an arylalkenyl group. The explanation of
R.sup.1 to R.sup.3 in the phosphoramide compound of the present
invention is applicable to the types and structures of the
above-mentioned alkyl group, alkenyl group, alkynyl group, aryl
group, arylalkyl group and arylalkenyl group.
[0106] In the general formula (11) described above, R.sup.10 and
R.sup.11 are each independently monovalent hydrocarbon groups.
Examples of the monovalent hydrocarbon group include an alkyl
group, an alkenyl group, an alkynyl group, an aryl group, an
arylalkyl group and an arylalkenyl group. The explanation of
R.sup.1 to R.sup.3 in the phosphoramide compound of the present
invention is applicable to the types and structures of the
above-mentioned monovalent hydrocarbon group, alkyl group, alkenyl
group and alkynyl group. R.sup.10 may be the same as or different
from R.sup.11. In the general formula (11) described above,
R.sup.10 and R.sup.11 can be each independently monovalent
hydrocarbon groups, and at least one of them can be an alkyl,
alkenyl or alkynyl group.
[0107] In the general formula (12) described above, R.sup.12 and
R.sup.13 are each independently aryl group, arylalkyl group or
arylalkenyl group. Additionally, in the general formula (13)
described above, R.sup.14 and R.sup.15 are each independently alkyl
group, alkenyl group or alkynyl group. The explanation of R.sup.1
to R.sup.3 in the phosphoramide compound of the present invention
is applicable to the types and structures of the above-mentioned
alkyl group, alkenyl group, alkynyl group, aryl group, arylalkyl
group and arylalkenyl group. Additionally, R.sup.12 may be the same
as or different from R.sup.13. R.sup.14 may be the same as or
different from R.sup.15.
[0108] The amount and proportion of each component to be used are
not particularly limited in the method for producing an optically
active alcohol of the present invention. For example, the amount of
the organozinc compound represented by the general formula (11) can
usually be in the range from 1 to 5 equivalents, preferably 1 to 4
equivalents, and more preferably 1 to 3 equivalents, based on the
above-mentioned carbonyl compound such as a ketone compound and an
aldehyde compound. Similarly, the amount of the organozinc compound
represented by the general formula (12) can usually be in the range
from 1 to 3 equivalents, preferably 1 to 2 equivalents, and more
preferably 1 to 1.5 equivalents. In addition, the amount of the
organozinc compound represented by the general formula (13) can
usually be in the range from 1 to 4 equivalents, preferably 1 to 3
equivalents, and more preferably 1 to 2.5 equivalents. Further, the
equivalent ratio of the organozinc compound represented by the
general formula (12) to the organozinc compound represented by the
general formula (13) can usually be 1:(1 to 5), preferably 1:(1 to
4), more preferably 1:(1 to 3), and further preferably 1:(1 to
2).
[0109] Further, the amount of the phosphoramide compound of the
present invention to be added can be usually in the range from 0.1%
to 20% by mol, preferably from 0.5% to 15% by mol, more preferably
from 1% to 15% by mol, and further preferably from 5% to 15% by mol
based on the above-mentioned carbonyl compound such as ketone
compound and aldehyde compound in the method for producing an
optically active alcohol of the present invention.
[0110] The reaction conditions of the method for producing an
optically active alcohol of the present invention are not
particularly limited. The reaction time is usually in the range
from 6 to 48 hours, preferably from 12 to 36 hours, more preferably
from 18 to 24 hours. The reaction temperature is usually in the
range from 0.degree. C. to 70.degree. C., preferably from
10.degree. C. to 50.degree. C., more preferably from 15.degree. C.
to 40.degree. C., and further preferably from 20.degree. C. to
30.degree. C.
[0111] The production of an optically active alcohol of the present
invention may be performed in the presence or absence of a solvent.
The method is preferably performed in the absence of a solvent
because an optically active alcohol can be obtained with a high
yield. Moreover, this method is preferably performed in the
presence of a solvent because a solid carbonyl compound such as a
solid ketone compound, and the like can be used as a starting
material. Examples of the solvent include hexane, heptane and
toluene. The solvent may be used singly or in combination of two or
more types thereof. The solvent may further contain an alcohol such
as methanol and ethanol for the improvement of the yield.
[0112] A titanium additive such as Ti(Oi-Pr).sub.4 is not
necessarily used as a reaction accelerator in the method for an
optically active alcohol of the present invention. Conventionally,
an equimolar or excess amount of the titanium additive was used as
a reaction accelerator. However, such a titanium additive is not
easy to handle because of strong moisture-absorption resolvability.
Since the titanium additive is not necessarily used in the present
invention, the production of an optically active alcohol can be
readily performed. Of course, such a titanium additive may be used
in the present invention. However, the amount of the titanium
additive used can be 2 equivalents or less, preferably 1 equivalent
or less, more preferably 0.5 equivalent or less, further preferably
0.3 equivalent or less, and particularly 0.1 equivalent or
less.
[0113] An alkyne can be further mixed in the method for the
production of an optically active alcohol of the present invention.
When an alkyne is mixed, an alkynyl group derived from the alkyne
can be added to the above-mentioned carbonyl compound such as an
aldehyde and a ketone. This is presumably because an alkynyl zinc
generated by reaction of the added organozinc compound with the
above-mentioned alkyne is coordinated to the ligand of the present
invention, forming a complex, followed by reaction of the complex
with the above-mentioned carbonyl compound (note that this
consideration is the inventor's presumption; therefore, this
conclusion is not intended to limit the scope of the present
invention). That is, the organic group in the organozinc compound
may be the same as or different from the organic group added to the
above-mentioned carbonyl compound in the method for the production
of an optically active alcohol of the present invention.
[0114] The type and structure of the optically active alcohol
obtained by the present invention are not particularly limited. Not
only an asymmetric alkylation reaction but also an asymmetric
phenylation reaction is possible in the method for the production
of an optically active alcohol of the present invention. Moreover,
various organozinc compounds can be used in the method for the
production of an optically active alcohol of the present invention.
As a result, various kinds of optically active alcohols having
various structures can be produced.
EXAMPLE
[0115] Hereinafter, the present invention is specifically described
using Examples, however, the present invention is not limited to
the embodiments by Examples. The embodiments in the present
invention can be varied in the range thereof according to the
purpose, application and the like.
<A> Synthesis of Optically Active Tertiary Alcohol Using
Phosphoramide Compound
(1) Synthesis of Phosphoramide Compound
[0116] Phosphoramide compounds (L1) and (L2) represented by the
following chemical formulae were synthesized according to the
method below. The structures of the phosphoramide compounds (L1)
and (L2) and their synthetic schemes are as follows.
##STR00016##
<Synthesis of Amide (2) Using Amino Acid Derivative (1)>
[0117] 100 ml of dehydrated methylene chloride was added to a
reaction vessel containing 4.25 g (20.0 mmol) of an amino acid
derivative (1) under a nitrogen atmosphere to dissolve the amino
acid derivative (1). 4.54 g (22.0 mmol) of dicyclohexylcarbodiimide
(DCC) and 2.97 g (22.0 mmol) of 1-hydroxybenzotriazole (HOBt) were
then added. The above-mentioned amino acid derivative (1) is an
amino acid derivative in which the nitrogen atom of L-valine is
protected with a tert-butoxycarbonyl group (Boc).
[0118] Subsequently, the solution was cooled to 0.degree. C., and
3.67 ml (44.0 mmol) of pyrrolidine was added dropwise over 10
minutes. After dropping, the mixture was stirred at 0.degree. C.
for 15 minutes, and warmed to room temperature, followed by further
stirring for 24 hours.
[0119] The completion of the reaction was confirmed by a TLC, and
the mixture was cooled to 0.degree. C. After that, 20 ml of a 10%
citric acid aqueous solution was added and stirred for 10 minutes,
followed by warming to room temperature. Extraction from the
mixture was performed twice using 50 ml of chloroform. The
extracted organic layer was washed with 20 ml of a 10% citric acid
aqueous solution and 20 ml of a saturated sodium chloride aqueous
solution, and dried with magnesium sulfate. The extracted organic
layer was filtered using "Celite" (trade name), and the solvent was
distilled off under reduced pressure. The obtained concentrated
liquid was purified by passing through silica gel column
chromatography (hexane/ethyl acetate=(3/1) to (1/1)), and thus
amide (2) was obtained. The yield of the amide (2) was 82% (4.43
g).
<Synthesis of Diamine (3) Using Amide (2)>
[0120] Methanol was added to a reaction vessel containing the
obtained amide (2) to dissolve the amide (2), and the solution was
cooled to 0.degree. C. 20 ml of acetyl chloride was added dropwise
to the mixture over 10 minutes. After dropping, the mixture was
stirred at 0.degree. C. for 3 hours, warmed to room temperature,
and further stirred for 1 hour. Subsequently, the solvent was
distilled off under reduced pressure, and Boc-deprotected amine was
obtained quantitatively. The Boc-deprotected amine was used in the
next reaction without purification.
[0121] 3.8 g (100 mmol) of lithium aluminum hydride was added to a
reaction vessel equipped with a reflux condensor under a nitrogen
atmosphere. After the reaction vessel was cooled to 0.degree. C.,
100 ml of dehydrated tetrahydrofuran (THF) was added. Then, 50 ml
of the obtained tetrahydrofuran solution containing the
Boc-deprotected amine was added dropwise over 10 minutes into the
mixture. After dropping, the reaction mixture was stirred at
0.degree. C. for 30 minutes and then refluxed for 48 hours.
[0122] The completion of the reaction was confirmed by a TLC, and
the mixture was cooled to 0.degree. C. 10 g of sodium sulfate and
20 ml of water were carefully added dropwise while vigorously
stirring the mixture. After dropping, the mixture was stirred at
0.degree. C. for 30 minutes and filtered using "Celite" (trade
name). The residue was washed with diethyl ether, and then the
collected organic layer was distilled off under reduced pressure.
The obtained concentrated liquid was purified by passing through
basic silica gel column chromatography (hexane/ethyl acetate=(3/1)
to (1/1)), and thus diamine (3) was obtained. The yield of the
diamine (3) was 61% (1.56 g).
<Synthesis of Phosphoramide Compound (L1) Using Diamine
(3)>
[0123] 20 ml of tetrahydrofuran was added to a reaction vessel
containing the diamine (3) under a nitrogen atmosphere. 2.22 g
(22.0 mmol) of triethylamine was then added, and the reaction
vessel was cooled to 0.degree. C. After cooling, 2.60 g (11.0 mmol)
of diphenylphosphinic acid chloride was added dropwise over 5
minutes. After dropping, the mixture was stirred at 0.degree. C.
for 30 minutes, warmed to room temperature, and further stirred for
3 hours. The completion of the reaction was confirmed by a TLC, and
the mixture was cooled to 0.degree. C. Subsequently, 10 ml of water
was added and warmed to room temperature. Extraction from the
mixture was performed twice using 20 ml of chloroform. The
extracted organic layer was washed with 10 ml of a saturated sodium
chloride aqueous solution, and dried with magnesium sulfate. The
filtration was performed using "Celite" (trade name) and the
solvent was distilled off under reduced pressure. The obtained
concentrated liquid was purified by passing through basic silica
gel column chromatography (hexane/ethyl acetate=(3/1) to (1/1)),
and thus the phosphoramide compound (L1) was obtained. The yield of
the phosphoramide compound (L1) was 86% (3.06 g).
[0124] The spectrum data of the phosphoramide compound (L1) was as
follows:
##STR00017##
(S)-N-(3-Methyl-1-(1-pyrrolidinyl)2-butanyl)diphenylphosphinic
amide (L1):
[0125] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.84 (d, J =6.3
Hz, 3H), 0.91 (d, J =6.3 Hz, 3H), 1.68-1.78 (m, 4H), 1.97 (m, 1H),
2.41-2.56 (m, 4H), 2.63-2.73 (m, 1H), 3.31 (m, 1H), 3.46 (br, 1H),
7.38-7.50 (m, 6H), 7.85-7.95 (m, 4H).
[0126] .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 17.6 (CH.sub.3),
18.2 (CH.sub.3), 23.5 (CH.sub.2), 30.3 (CH), 54.3 (CH.sub.2), 55.1
(CH), 57.5 (d, J =5.7 Hz, CH), 128.2, 128.4, 131.6, 132.0, 132.1,
132.2.
[0127] .sup.31P NMR (121 MHz, CDCl.sub.3) .delta. 23.9 (s, IR (KBr)
3158, 2957, 2777, 1590, 1458, 1354, 1283, 1179, 1107, 1049, 974
cm.sup.-1.
[0128] [.alpha.].sub.D.sup.20=-9.2 (c 1.00, THF).
[0129] The phosphoramide compound (L2) was synthesized in the same
manner as above.
[0130] .sup.31P-NMR (121 MHz) of the phosphoramide compound (L1)
was measured in methylene chloride. Next, one equivalent of
diethylzinc was added to the phosphoramide compound (L1), and
.sup.31P-NMR (121 MHz) was measured.
[0131] As a result, the phosphoramide compound (L1) gave a singlet
peak at 22.20 ppm. When one equivalent of diethylzinc was added to
this solution, a new singlet peak was observed at 23.38 ppm,
accompanied by the generation of one equivalent of ethane gas.
(2) Synthesis of Optically Active Tertiary Alcohol (I)--Ethylation
Reaction of Ketone
[0132] The phosphoramide compounds (L1) and (L2) were used as a
ligand. These ligands were added to react acetophenone with
diethylzinc and an optically active tertiary alcohol was
synthesized.
[0133] 3.0 ml (3.0 mmol) of diethylzinc (1.0 M heptane solution)
was added to a Schlenk reaction flask containing 45.6 mg (0.10
mmol) of the phosphoramide compound (L2) under a nitrogen
atmosphere, and stirred at room temperature for 30 minutes.
Subsequently, 120.2 mg (1.0 mmol) of acetophenone was added to the
reaction mixture, and stirred at room temperature for 24 hours.
[0134] The completion of the reaction was confirmed by a TLC. After
confirmation, the mixture was cooled to 0.degree. C. 10 ml of a
saturated aqueous ammonium chloride solution was then added and
warmed to room temperature. Extraction from the mixture was
performed twice using 15 ml of diethyl ether. The extracted organic
layer was washed with 10 ml of a saturated sodium chloride aqueous
solution, and dried with magnesium sulfate. Then, the filtration
was performed using "Celite" (trade name), and the solvent was
distilled off under reduced pressure.
[0135] The obtained concentrated liquid was purified by passing
through silica gel column chromatography (pentane/diethyl
ether=(10/1) to (2/1)), and thus an optically active tertiary
alcohol was obtained. The yield was 80% (120.1 mg). Further, the
enantiomeric excess of the obtained optically active tertiary
alcohol was measured by gas chromatography using a chiral column.
As a result, the enantiomeric excess was 93% ee (S).
[0136] An optically active tertiary alcohol was synthesized in the
same manner as above except that the phosphoramide compound (L1)
was used as a ligand instead of the phosphoramide compound (L2),
and that the reaction temperature was room temperature. As a
result, the yield was 21%, and the enantiomeric excess was 87% ee
(S). Meanwhile, an optically active tertiary alcohol was
synthesized in the same manner as above except that the reaction
temperature was changed from room temperature to 50.degree. C. As a
result, the yield was 32%, and the enantiomeric excess was 78% ee
(S).
[0137] The following optically active tertiary alcohols were
synthesized using the phosphoramide compounds (L1) and (L2) as a
ligand in the same manner as above. The structure of the
synthesized optically active tertiary alcohols, the reaction time
(h), yield (%), and enantiomeric excess (% ee) are indicated
below.
##STR00018##
(3) Synthesis of Optically Active Tertiary Alcohol
(II)--Phenylation Reaction of Ketone
[0138] 1.0 ml (3.0 mmol) of diphenylzinc (1.0 M heptane solution)
and 2.0 ml (2.0 mmol) of diethylzinc (1.0 M heptane solution) were
used instead of the diethylzinc in the method of synthesizing
optically active tertiary alcohols described in Section (2). Other
conditions were the same as in the synthesis method of Section (2),
and p-chloroacetophenone, diphenylzinc, and diethylzinc were
reacted to synthesize an optically active tertiary alcohol.
[0139] The following optically active tertiary alcohols were
synthesized in the same manner as above. The structure of the
synthesized optically active tertiary alcohols, the reaction time
(h), yield (%), and enantiomeric excess (% ee) are indicated
below.
##STR00019##
[0140] Further, optically active tertiary alcohols were synthesized
in the same manner as above except that the amount of the ligand
and the reaction temperature were changed. The results are shown
below.
##STR00020##
TABLE-US-00001 entry X mol % temperature time (h) yield (%) ee (%)
1 10 r.t. 8 87 88 2 10 0.degree. C. 30 78 93 3 3 r.t. 16 97 84 4 1
r.t. 40 82 81
[0141] Moreover, optically active tertiary alcohols were
synthesized in the same manner as above except that the amounts of
reactants (diphenylzinc and diethylzinc) were changed. The results
are shown below.
##STR00021##
TABLE-US-00002 entry X equiv. Y equiv. time (h) yield (%) ee (%) 1
1 2 8 87 88 2 0.75 2 16 63 86 3 0.5 2 24 42 85 4 1 1 8 68 86
(4) Synthesis of Optically Active Tertiary Alcohol (III)
[0142] The following phosphoramide compounds were synthesized in
the same manner as in Section (1). The obtained phosphoramide
compounds were used as a ligand instead of the phosphoramide
compounds (L1) and (L2) in the method of synthesizing optically
active tertiary alcohols described in Section (2). Other conditions
were the same as in the method of Section (2), and optically active
tertiary alcohols were synthesized in the same manner as in above
(2). The structure of the synthesized phosphoramide compounds, the
reaction time, yield, and enantiomeric excess are indicated
below.
TABLE-US-00003 Ligand Time(h)/Yield(%)/ee(%) ##STR00022##
##STR00023## ##STR00024## 24/53/80 (hep + hep) 8/94/81 (hex)
6/65/86 (tol) 8/87/88 (hep) ##STR00025## 24/61/64 (hex + hex)
24/24/74 (tol + hex) ##STR00026## 24/48/68 (hex + hex) ##STR00027##
24/38/85 (hex + hex) ##STR00028## 24/30/80 (hep + hep) ##STR00029##
24/44/78 (hep + hep) 8/98/82 (hep) ##STR00030## 24/52/77 (hex +
hex) ##STR00031## 24/68/82 (hex + hex) ##STR00032## 8/86/83 (hep)
##STR00033## 24/93/78 (hex + hex) ##STR00034## 24/42/77 (hep + hep)
##STR00035## 8/98/95 (hep) ##STR00036## 12/45/58 (hep) ##STR00037##
24/46/86 (hex + hex) ##STR00038## 24/31/65 (hex + hex) ##STR00039##
24/51/74 (hex + hex)
(5) Results of Examples
[0143] It is found from the spectrum data of the phosphoramide
compound (L1) and the generation of one equivalent of ethane gas,
that the phosphoramide compound (L1) and diethylzinc form a zinc
complex.
[0144] Moreover, this result suggests that the zinc complex is
presumably one represented by the general formula (C1) formed by
the following scheme (note that this consideration is the
inventor's presumption; therefore, this conclusion is not intended
to limit the scope of the present invention).
##STR00040##
[0145] Although optically active tertiary alcohols were
conventionally difficult to synthesize, they can be synthesized
with a high efficiency and high enantioselectivity by using the
phosphoramide compounds (L1) and (L2). In addition, optically
active tertiary alcohols can be synthesized with a high efficiency
and high enantioselectivity, without the addition of conventionally
used reactants such as titanium additives.
[0146] Comparing the phosphoramide compounds (L1) and (L2), the
yield as well as the enantiomeric excess is higher when the
phosphoramide compound (L2) is used. Accordingly, optically active
tertiary alcohols can be synthesized with a high efficiency and
high enantioselectivity by using the phosphoramide compound
(L2).
[0147] Additionally, various phosphoramide compounds of the present
invention were synthesized, and the alkyl addition reaction of a
ketone was performed using these phosphoramide compounds as a
ligand. As a result, tertiary alcohols were synthesized with a high
enantioselectivity using any of these ligands.
<B> Synthesis of Optically Active Secondary Alcohol using
Phosphoramide Compound (1) Synthesis of ligand
[0148] Ligands (L3) to (L12) represented by the following chemical
formulae were synthesized in the following manner. The structures
of the ligands (L3) to (L12) and their synthetic schemes are as
follows.
##STR00041## ##STR00042##
<Synthesis of Phosphoramide (2) Using Amino Acid Hydrochloride
(1)>
[0149] 50 ml of methylene chloride was added to a reaction vessel
containing 3.35 g (20 mmol) of an amino acid hydrochloride (1)
under a nitrogen atmosphere. 4.44 g (22 mmol) of triethylamine was
then added, and the reaction vessel was cooled to 0.degree. C.
After cooling, 5.20 g (22 mmol) of diphenylphosphinic acid chloride
was added dropwise over 5 minutes. After dropping, the mixture was
stirred at 0.degree. C. for 30 minutes, warmed to room temperature,
and further stirred for 3 hours. The completion of the reaction was
confirmed by a TLC, and the mixture was cooled to 0.degree. C. 20
ml of water was added and then the mixture was warmed to room
temperature. Extraction from the mixture was performed twice using
30 ml of chloroform. The extracted organic layer was washed with 20
ml of a saturated sodium chloride aqueous solution, and was dried
with magnesium sulfate. The filtration was performed using "Celite"
(trade name), and the solvent was distilled off under reduced
pressure. The obtained concentrated liquid was purified by passing
through silica gel column chromatography (hexane/ethyl
acetate=(3/1) to (1/1)), and thus phosphoramide (2) was obtained.
The yield of the phosphoramide (2) was 68% (4.51 g).
<Synthesis of Carboxylic Acid (3) Using Ester (2)>
[0150] 20 ml of 1,4-dioxane was added to a reaction vessel
containing 3.31 g (10 mmol) of the obtained phosphoramide (2). The
solution was then cooled to 0.degree. C., and 5.5 ml of 2M sodium
hydroxide aqueous solution was added dropwise over 10 minutes.
After dropping, the mixture was stirred at 0.degree. C. for 15
minutes, warmed to room temperature, and further stirred for 5
hours. The completion of the reaction was confirmed by a TLC, and
the mixture was cooled to 0.degree. C. Subsequently, a saturated
citric acid aqueous solution was added to adjust the pH of the
mixture between 3 and 4. Extraction from the mixture was performed
twice using 30 ml of ethyl acetate. The extracted organic layer was
washed with 20 ml of water and 20 ml of a saturated sodium chloride
aqueous solution, and dried with magnesium sulfate. The filtration
was performed using "Celite" (trade name), and the solvent was
distilled off under reduced pressure. The obtained crude product
was recrystallized using a solvent in which hexane and toluene were
mixed at a ratio of 1:1, and thus a carboxylic acid (3) was
obtained. The yield of the carboxylic acid (3) was 99% or more
(3.17 g).
<Synthesis of Alcohol (4) Using Carboxylic Acid (3)>
[0151] 908 mg (24 mmol) of sodium borohydride was added to a
reaction vessel equipped with a reflux condensor under a nitrogen
atmosphere. The reaction vessel was cooled to 0.degree. C., and
then 30 ml of dehydrated tetrahydrofuran (THF) was added. Next, 20
ml of a tetrahydrofuran solution containing 3.17 g (10 mmol) of the
above-mentioned carboxylic acid (3) was added into the vessel at
once. 10 ml of a tetrahydrofuran solution containing 2.54 g (10
mmol) of iodine was then added dropwise to the mixture over 10
minutes. After dropping, the reaction mixture was stirred at
0.degree. C. for 15 minutes and then refluxed for 18 hours. The
completion of the reaction was confirmed by a TLC, and the mixture
was cooled to 0.degree. C. Then, methanol was carefully added
dropwise until the reaction mixture became homogenized. After the
dropping was completed, the mixture was stirred at 0.degree. C. for
30 minutes, and the solvent was distilled off under reduced
pressure. 20 ml of a 20% potassium hydroxide aqueous solution was
added to the obtained concentrated liquid. After the mixture was
stirred at room temperature for 4 hours, extraction was performed
twice using 50 ml of chloroform. The extracted organic layer was
washed with 20 ml of water and 20 ml of a saturated sodium chloride
aqueous solution, and dried with magnesium sulfate. The filtration
was performed using "Celite" (trade name), and the solvent was
distilled off under reduced pressure. The obtained concentrated
liquid was purified by passing through silica gel column
chromatography (hexane/ethyl acetate=(3/1) to (1/1)), and thus an
alcohol (4) was obtained. The yield of the alcohol (4) was 47%
(1.42 g).
[0152] <Synthesis of Amide (5) Using Carboxylic Acid (3)>
[0153] 50 ml of dehydrated methylene chloride was added to a
reaction vessel containing 3.17 g (10 mmol) of the obtained
carboxylic acid (3) under a nitrogen atmosphere to dissolve the
acid. Subsequently, 2.27 g (11 mmol) of DCC and 1.48 g (11 mmol) of
HOBt were then added. The mixture was then cooled to 0.degree. C.,
and 2.17 ml (22 mmol) of piperidine was added dropwise over 10
minutes. After dropping, the mixture was stirred at 0.degree. C.
for 15 minutes, warmed to room temperature, and further stirred for
24 hours. The completion of the reaction was confirmed by a TLC,
and the mixture was cooled to 0.degree. C. After 10 ml of a 10%
citric acid aqueous solution was added, the mixture was stirred for
10 minutes and warmed to room temperature. Extraction from the
mixture was performed twice using 30 ml of chloroform. The
extracted organic layer was washed with 10 ml of a 10% citric acid
aqueous solution and 10 ml of a saturated sodium chloride aqueous
solution, and dried with magnesium sulfate. The filtration was
performed using "Celite" (trade name), and the solvent was
distilled off under reduced pressure. The obtained concentrated
liquid was purified by passing through silica gel column
chromatography (hexane/ethyl acetate=(3/1) to (1/1)), and thus an
amide (5) was obtained. The yield of the amide (5) was 62% (2.38
g).
<Synthesis of Amine (6) Using Amide (5)>
[0154] 152 g (40 mmol) of lithium aluminum hydride was added to a
reaction vessel equipped with a reflux condensor under a nitrogen
atmosphere. The reaction vessel was cooled to 0.degree. C., and
then 40 ml of dehydrated tetrahydrofuran (THF) was added.
Subsequently, 20 ml of the tetrahydrofuran solution containing the
obtained amide (5) was added dropwise over 10 minutes. After
dropping, the reaction mixture was stirred at 0.degree. C. for 30
minutes and then refluxed for 48 hours. The completion of the
reaction was confirmed by a TLC, and the mixture was cooled to
0.degree. C. Then, 4 g of sodium sulfate and 10 ml of water were
carefully added dropwise while vigorously stirring the mixture.
After dropping, the mixture was stirred at 0.degree. C. for 30
minutes and filtered using "Celite" (trade name). The residue was
washed with diethyl ether, and the collected organic layer was
distilled off under reduced pressure. The obtained concentrated
liquid was purified by passing through basic silica gel column
chromatography (hexane/ethyl acetate=(3/1) to (1/1)), and thus an
amine (6) was obtained. The yield of the amine (6) was 57% (1.30
g).
(2) Synthesis of Optically Active Secondary Alcohol
[0155] The phosphoramide compound (L1) and the ligands (L3) to
(L12) were used as a ligand. Each of these ligands was added, and
benzaldehyde and diethylzinc were reacted to synthesize an
optically active secondary alcohol.
[0156] 3.0 ml (3.0 mmol) of diethylzinc (1.0 M toluene solution)
was added to a Schlenk reaction tube containing 0.10 mmol of the
phosphoramide compound (L1) or the ligands (L3) to (L12) under a
nitrogen atmosphere, and stirred at 0.degree. C. for 30 minutes.
Then, 1.0 mmol of benzaldehyde was added to the reaction solution
and stirred at 0.degree. C. for 24 hours.
[0157] The completion of the reaction was confirmed by a TLC. After
confirmation, 10 ml of a saturated aqueous ammonium chloride
solution was added and warmed to room temperature. Extraction from
the mixture was performed twice using 15 ml of diethyl ether. The
extracted organic layer was washed with 10 ml of a saturated sodium
chloride aqueous solution, and dried with magnesium sulfate. Then,
the filtration was performed using "Celite" (trade name), and the
solvent was distilled off under reduced pressure.
[0158] The obtained concentrated liquid was purified by passing
through silica gel column chromatography(pentane/diethyl
ether=(10/1) to (2/1)), and thus an optically active secondary
alcohol was obtained. The structure of the synthesized optically
active secondary alcohol, the reaction time, yield, and
enantiomeric excess are indicated together with the structure of
each of the above ligands.
[0159] Optically active secondary alcohols can be synthesized from
an aldehyde compound by using the phosphoramide compound (L1) and
the ligands (L3) to (L12). Moreover, optically active secondary
alcohols can be synthesized with a high efficiency and high
enantioselectivity, without the addition of conventionally used
reactants such as titanium additives. The phosphoramide compound
(L1) is effective in synthesis of both optically active secondary
alcohols and optically active tertiary alcohols.
[0160] When the ligands (L3) to (L7) (ester) are used, higher yield
and higher enantioselectivity are provided rather than when the
ligand (L8) (carboxylic acid) and ligand (L9) (alcohol) are used.
Moreover, when the ligands (L3) to (L6) are used, higher
enantioselectivity is provided rather than when the ligand (L7) is
used. Furthermore, when the ligand (L6) is used, higher yield is
provided rather than when the ligand (L3) is used.
[0161] The ligand (L11) in which amide is reduced ensures higher
enantioselectivity rather than the ligand (L10) having an amide
structure. Moreover, the tertiary amine (L12) is superior to the
secondary amine (L10) in both the yield and enantioselectivity.
[Industrial Applicability]
[0162] The present invention is useful for synthesizing an
optically active alcohol from a carbonyl compound such as an
aldehyde compound and ketone compound, particularly a ketone
compound, with a high efficiency and high enantioselectivity. The
optically active alcohol synthesized by the present invention is
useful as drugs and pesticides, or synthetic intermediates thereof.
For example, drugs (e.g., clemastine that is often used as an
antihistamine) can be synthesized without an optical resolution
process, which was essential in the past, by using the optically
active alcohols synthesized by the present invention.
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