Field of the Invention
This invention relates to an optically active hydroxymethylation
reaction. More particularly, this invention relates to a method for manufacturing
an optically active hydroxymethylated compound and a catalyst used for the method
in a water solvent.
Background of the Invention
Many useful compounds and intermediates thereof containing
hydroxymethyl groups on the asymmetric carbon are known. As methods to synthesize
these optically active hydroxymethylated compounds, a derivation method (Non-patent
Reference 1) using readily available optically active compounds, an optical resolution
method (Non-patent References 2 and 3) and a diastereoselective asymmetric synthesis
reaction (Non-patent Reference 4) have previously been used. With recent progress
in asymmetric synthesis methods, an increasing number of reports about catalytic
asymmetric hydroxymethylation reactions have been published. However, problems such
as substrate generality, yield, stereoselectivity and the like remain (Non-patent
References 5-7, Patent Reference 1).
Formaldehyde, on the other hand, is the most important electrophilic agent used
in organic syntheses to increase the number of carbon atoms by one, and methods
in which formaldehyde is activated using a Lewis acid are frequently used in hydroxymethylation
reactions. However, when a reaction is conducted in an organic solvent formaldehyde
needs to be generated from a formaldehyde polymer through thermal decomposition
causing serous safety and convenience problems. Formalin, that is, an aqueous solution
of formaldehyde, is inexpensive and easy to handle, but formalin is difficult to
activate using a Lewis acid since Lewis acids are ordinarily readily hydrolyzed.
The inventors recently discovered that rare earth metal
salts are stable in aqueous solutions and function as Lewis acids, and the inventors
executed hydroxymethylation reactions in aqueous solutions (Non-patent Reference
8). Furthermore, the inventors recently discovered that a chiral scandium complex
was effective in a catalytic asymmetric hydroxymethylation reaction conducted using
formalin in an aqueous solution (Non-patent Reference 9).
Similarly, bismuth salts exhibit highly Lewis acid type characteristics and are
known to show catalytic activities better than those of scandium depending on reaction
type (particularly in reactions conducted in aqueous solutions). In addition, the
bismuth cation is almost non-toxic and is less expensive than scandium. However,
the cyanolation reaction of aldehydes using trimethylsilyl cyanide in methylene
chloride is the only catalytic asymmetric reaction known conducted using a bismuth
salt (Non-patent Reference 10).
- [Non-patent Reference 1]
Kaku, K. et al., Chem. Pharm. Bull., 46, 1125 (1998
).
- [Non-patent Reference 2]
Wu, C. et al., Tetrahedron, 57, 9575 (2001
)
- [Non-patent Reference 3]
Kumar, R. et al., Bioorg. Med. Chem., 9, 2643 (2001
)
- [Non-patent Reference 4]
Reynolds, A. et al., J. Am. Chem. Soc., 125, 12108 (2003
)
- [Non-patent Reference 5]
Ito, Y. et al., Chem. Commun., 1998, 71
- [Non-patent Reference 6]
Yamamoto, H. et al., Synlett, 2003, 2219
- [Non-patent Reference 7]
Cordova, A. et al., Tetrahedron Lett., 45, 6117 (2004
)
- [Patent Reference 1]
Japanese laid-open application publication (Kokai) No. 2002-200428
- [Non-patent Reference 8]
Kobayashi, S. et al., Chem. Lett., 1991, 2187
- [Non-patent Reference 9]
Ishikawa, S. et al., J. Am. Chem. Soc., 126, 12236 (2004
)
- [Non-patent Reference 10]
Wada, M. et al., Tetrahedron: Asymmetry, 8, 3939 (1997
)
Disclosure Of the Invention
Problems to be solved by the invention
Based on experience, the object of this invention is to
present a method to manufacture optically active hydroxymethylated compounds with
a broad substrate generality, in high yields and with excellent stereoselectivity
when using formaldehyde as the electrophilic agent in aqueous solutions.
Means to solve the Problems
In order to solve the problems, the inventors investigated
the aldol reactions of silicon enolates using formaldehyde, such as formalin and
the like, as the electrophilic agent. As a result, the inventors discovered that
said reaction proceeded with excellent yield and stereoselectivity when an asymmetric
catalyst prepared from a bismuth salt and an optically active bipyridine compound
was used. This invention was completed based on the discovery.
That is, this invention is a method for manufacturing an
optically active hydroxymethylated compound that allows a silicon enolate represented
by the following formula (Formula 1)
(in the formula, R5 to R7 represent hydrogen atoms, aliphatic
hydrocarbon groups, monocyclic or polycyclic alicyclic hydrocarbon groups, monocyclic
or polycyclic aromatic or aromatic-aliphatic hydrocarbon groups or heterocyclic
groups, R5 and R7 are different, R6 is not a hydrogen
atom, each R8 may be identical or different and represents a methyl group,
ethyl group or isopropyl group) and formaldehyde to react in an aqueous solution
or in a mixed solvent of water and an organic solvent or in a mixed solvent of water
and organic solvents in the presence of a catalyst obtained by blending a ligand
comprising a chiral bipyridine compound or its antipode and a Lewis acid represented
by BiY3 (in the formula, Y represents a halogen atom, OAc, OCOCF3,
ClO4, SbF6, PF6 or OSO2CF3).
Said ligand comprising the chiral bipyridine compound is
preferably represented by the following formula (Chemical Formula 2).
(In the formula, R1 represents an alkyl group containing
four or fewer carbon atoms or a phenyl group.)
The molar ratio represented by (said ligand comprising
the chiral bipyridine or its antipode/said Lewis acid) is preferably at least 2.5.
The addition of 2,2'-bipyridine as an additive is preferred.
In addition, this invention is a catalyst obtained by mixing
a ligand comprising a chiral bipyridine compound or its antipode and Bi(OTf)3.
According to this invention, a compound with hydroxymethyl
groups bonded to an asymmetric carbon useful, for example, in starting materials
or synthetic intermediates for pharmaceutical products, lead compounds and the like
can be obtained in high yields and with excellent stereoselectivity in an aqueous
solvent by using formaldehyde (for example, formalin) and a bismuth salt as inexpensive
and safe starting materials.
Best mode for carrying out the invention
The catalyst used in this invention can be obtained by
mixing a ligand comprising a chiral bipyridine compound or its antipode and a Lewis
acid represented by BiY3 (in the formula, Y represents a halogen atom,
OAc, OCOCF3, ClO4, SbF6, PF6 or OSO2CF3).
The ligands comprising bipyridine compounds or their antipodes
contain two asymmetric carbons bonded to hydroxyl groups and become chiral ligands
that control the catalytic activity of a Bi salt in water. The bipyridine compound
has a suitable coordination capacity for a Bi salt, does not reduce Lewis acidity
and maintains the stereoselectivity of the catalyst without releasing too much cation
from the complex comprising the Bi and the ligand.
The use of a bipyridine compound represented by the following formula (Chemical
Formula 2) is particularly preferred from the standpoint of Lewis acidity and stereoselectivity.
(In the formula, R1 represents an alkyl group containing four or fewer
carbon atoms or a phenyl group.)
A Lewis acid represented by BiY3 is used as
the bismuth salt. Y represents a halogen atom, OAc, OCOCF3, ClO4,
SbF6, PF6 or OSO2CF3 (OTf). Of these,
Bi(OTf)3 is effective. In addition, bismuth cation has an extremely low
toxicity and is also less expensive than scandium.
When the ligand is mixed with BiY3 in a solvent,
the Bi salt becomes coordinated with the ligand to form a catalyst. As the solvent,
aprotic polar solvents that are readily miscible with water, and mixtures of said
solvents with water may be listed as examples. As the aprotic polar solvents, ethers
such as DME (dimethoxyethane), diglyme (diethylene glycol dimethyl ether) and the
like; nitriles such as propionitrile and the like and ketones such as acetone and
the like may be cited. These organic solvents may be mixed in a proportion of 1
to 19 (volume ratio) per one of water.
The individual concentrations of the ligands and BiY3, such as Bi(OTf)3
and the like, of about 0.01 to 0.1 moles/liter in a solvent is preferred.
In this invention, this catalyst is used in an asymmetric
hydroxymethylation reaction (Chemical Equation 3) of formaldehyde and the silicon
enolates described below.
R5 to R7 represent hydrogen atoms, aliphatic hydrocarbon groups,
monocyclic or polycyclic alicyclic hydrocarbon groups, monocyclic or polycyclic
aromatic or aromatic-aliphatic hydrocarbon groups or heterocyclic groups, and they
may also contain substituents. As the hydrocarbon groups or heterocyclic groups,
alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl and the like, cyclohexyl
groups, phenyl groups, phenyl ethyl groups, phenyl vinyl groups, naphthyl groups,
furyl groups, thienyl groups and the like, for example, may be listed as examples.
In addition, the substituents that also may be present may be halogen atoms, alkoxy
groups, thioalkoxy groups, hydrocarbon groups and the like.
R5 to R7 are preferably as listed below.
R5 represents a hydrogen atom or an alkyl group, R6 represents
an alkyl group, alkyl aryl group, aryl group or sulfide group. However, a section
of R5 and R6 may together form a five to six membered ring
comprising carbon and optional hetero atoms or preferably carbon atoms part of which
may form an aromatic ring. R7 represents a hydrogen atom, an alkyl group,
an alkyl aryl group or an aryl group.
In addition, R5 and R7 are different.
Each R8 represents a hydrocarbon group. These
may be identical or different, but identical groups are preferred. R8
is a methyl group, ethyl group or isopropyl group.
The reaction is allowed to occur in an aqueous solution
or a mixed solvent of water and an organic solvent. At this point, the organic solvent
used in the form of a mixed solvent with water may be dimethoxyethane (DME), tetrahydrofuran
(THF), acetonitrile, dioxane and the like that easily blend with water, but DME,
THF, acetonitrile and dioxane can be listed as preferred examples. The mix ratio
for the organic solvent and water is not particularly restricted, but the mixed
solvent generally contains at least 1 % by weight and more preferably at least 5%
by weight of water.
The amount of the aqueous solution or the mixed solvent
used may be appropriately selected. Ordinarily, however, a proportion of two to
fifty weight fold is considered, for example, as the amount needed to dissolve the
starting material substances and the catalyst.
The HCHO/silicon enolate molar ratio in a reaction solution
is preferably one to fifty and more preferably about one to ten. In addition, the
catalyst is used at 1 to 50 mole % of the silicon enolate and is more preferably
used at 5 to 20 mole %.
The reaction temperature is -30°C to ambient temperature, and a more ideal
range is -15 to 0°C.
The reaction time may be decided appropriately, and 0.5 to 50 hours, for example,
may be used.
An optically active hydroxymethylated compound is formed
using this reaction.
In the method of this invention, a molar ratio of at least
2.5 is preferred and at least three is more preferred for the (said ligand comprising
the chiral bipyridine compound or its antipode/said Lewis acid). When said molar
ratio is less than 2.5, the product yield and selectivity tend to decline. The most
preferred range for said molar ratio is three to four.
Moreover, the addition of 2,2'-bipyridine as an additive
is preferred in the method of this invention. When the reaction described above
is allowed to occur upon adding 2,2'-bipyridine, the amount of the catalyst added
can be reduced without adversely affecting the yield and the selectivity. As the
amount of 2,2'-bipyridine added, at least five moles per mole of said bismuth salt,
for example, is preferred. When the amount of 2,2'-bipyridine added is three moles
or less, the product yield tends not to improve sufficiently. In addition, when
the amount added exceeds five moles, the effect becomes saturated.
The present invention is illustrated in the following examples,
but these examples are not intended to limit the scope of the present invention.
Example 1
A chiral bipyridine with the structure of the following
formula (Chemical Formula 2) was prepared according to the method described in Non-patent
Reference 3.
DME (0.50 ml) was added to a metal salt, MXn (0.020 mmole of the compounds
listed in Table 1 below), that had been dried for an hour at 200°C under vacuum.
The ligand 1a described above [R1 = tert-Bu, 0.022 mmole in a compound
of the formula above (Chemical Formula 2)] was added to this solution, and the mixture
was agitated at room temperature until the mixture was clear. The temperature of
the solution was lowered to 0°C, and an aqueous HCHO solution (35%, 86 mg,
1.0 mmole) and silicon enolate 2 [a compound (0.20 mmole) of the following chemical
formula (Chemical Formula 4)] was added. A saturated aqueous sodium bicarbonate
solution was added after four hours of agitation, and three CH2Cl2
extractions of the aqueous layer were performed. The organic layer was dried using
Na2SO4, the solvent was removed by distillation under reduced
pressure and the residue was purified using silica gel thin layer chromatography
(hexane:AcOEt = 2:1). The volume ratio of water/DME was 1/9.
The results obtained are shown in Table 1. In the table,
the term "trace" signifies that a substance was almost not detected. In addition,
Ee indicates the enantiomer excess ratio.
[Table 1]
Experimental Examples
MXn
Yield (%)
Ee(%)
1
Fe(OTf)3
25
20
1
Cu(OTf)2
8
-58
3
AgOTf
trace
53
4
Cd(ClO4)2
4
0
5
Yb(OTf)3
4
32
6
Zn(OTf)2
8
0
7
Pb(OTf)2
10
10
8
Ga(OTf)3
3
0
9
Sb(OTf)3
trace
18
10
In(OTf)3
10
64
11
Sc(OTf=3
70
84
12
Bi(OTf)3
78
92
13
BiF3
0
-
14
BiCl3
trace
0
15
BiBr3
trace
2
16
Bil3
5
16
The results reported in Table 1 indicate that the product
yields were high and Ee was also high when scandium triflate and bismuth triflate
were used (Experimental Examples 11 and 12).
Example 2
Exactly the same procedure described in Example 1 was used
with the exception that Bismuth triflate, 3 mole %, was used as the metal salt,
and 9 mole % of the ligand 1 a was used and furthermore the solvents indicated in
Table 2 were used in place of DME.
The results obtained are reported in Table 2. The symbols
used in the table had the same significance described in Table 1.
[Table 2]
Experimental Examples
Solvent
Yield (%)
Ee(%)
17
DME
67
92
18
THF
32
80
19
EtOH
trace
65
20
H2O
7
46
21
DMF
5
46
22
Propionitrile
51
85
23
Ethylene glycol
trace
-8
24
Diglyme
58
89
25
Acetone
74
90
According to the results reported in Table 2, the product
yield was high and Ee was also high when DME (dimethoxyethane, Experimental Example
17), propionitrile (Experimental Example 22), diglyme (Experimental Example 24)
and acetone (Experimental Example 25) were used.
Example 3
Exactly the same procedure described in Example 1 was used
with the exception that the amounts of bismuth triflate and ligand 1a were changed
and, in addition, the reaction temperature was changed. However, the silicon enolate
concentration was 0.36 M.
The results obtained are reported in Table 3. The symbols
used in the table have the same significance as described in Table 1. Now, the amount
of bismuth triflate was X% by mole, the amount of ligand 1 a was Y% by mole and
the reaction temperature was T°C as shown in the table.
[Table 3]
Experimental Example
X
Y
T
Yield (%)
Ee(%)
26
10
30
0
92
93
27
5
15
0
81
92
28
3
9
0
67
92
29
3
9
10
76
92
30
1
3
0
63
92
31a)
1
3
0
73
92
a) [Silicon enolate] = 0.72
M
According to the results reported in Table 3, the stereoselectivity
was good in all of Experimental Examples 26 to 31 even when the conditions were
changed. In addition, the yield improved in Experimental Example 29 compared to
Experimental Example 28 when the reaction temperature was raised. In addition, the
yield improved in Experimental Example 26 compared to Experimental Example 27 when
the substrate concentration was raised.
Example 4
Exactly the same procedure described in Example 1 was
used with the exception that the amount of ligand 1 a in relation to bismuth triflate
was changed.
Now, the chemical formula of ligand 1 a in all of the examples
is represented by Chemical Formula 8.
The results obtained are reported in Table 4. The symbols
used in the table have the same significance as described in Table 1. Now, the amount
of bismuth triflate was 10 mole % in the table, and the amount of ligand 1a is represented
as Y mole %.
[Table 4]
Experimental Example
Y
Yield (%)
Ee(%)
32
5
6
44
33
10
18
71
34
12
26
78
35
15
33
80
36
20
36
84
37
24
72
91
38
30
92
93
39
40
84
91
According to the results reported in Table 4, the yield
and Ee were high in Experimental Examples 37 to 39 when the molar ratio, [ligand
1a (mole %)/bismuth triflate (mole %)], was at least 2.4. The highest yield and
Ee were observed in Experimental Example 38 when the ratio described above was three.
Example 5
Furthermore, exactly the same procedure described in Example
1 was used with the exception that a five fold molar ratio of 2,2'-bipyridine to
the bismuth salt was added as an additive and the proportions of bismuth triflate
and ligand 1a and the reaction time were changed (Experimental Examples 43 and 44).
The results obtained are reported in Table 5. The symbols
used in the table have the same significance as described in Table 1. Now, the amount
of bismuth triflate was represented by X mole % in the table, and the amount of
ligand 1a was represented as Ymole %.
[Table 5]
Experimental Example
solvent
x
y
time (h)
yield
a
(%)
eeb (%)
40
H2O/DME = 1/9
10
30
4
92
93
41
H2O/DME = 1/9
3
9
4
67
92
42
H2O/DME = 119
1
3
4
63
83
43
a
)
H2O/DME = 1/9
1
3
21
93
91
44
b)
H2O/DME = 1/9
0.5
1.5
16
76
90
a) 5 mol % of 2,2'-bipyridine was added.
b) 2.5 mol % of 2,2'-bipyridine was added.
Now, Experimental Examples 40, 41 and 42 were identical to Experimental Examples
26, 28 and 30, respectively.
According to the results reported in Table 5, the yield
and Ee both declined when the amount of catalyst used was decreased (Experimental
Examples 40 to 42). In Experimental Example 42, silicon enolate, one of the substrates,
disappeared four hours after the reaction started and the reaction stopped (yield
63%). In contrast, the reaction proceeded while silicon enolate still remained twenty-one
hours after the reaction started, the yield improved significantly and Ee also rose
in Experimental Example 43 when 2,2'-bipyridine was also added, although the values
of x and y were identical to those of Experimental Example 42. The yield decreased
slightly, but the selectivity was maintained in Experimental Example 44 when the
amount of catalyst (represented by x in the table) was further decreased to 0.5
mole %.
Example 6
A reaction was allowed to occur using exactly the same
procedure as that of Example 1 with the exception that various substrates were used
and 2,2'-bipyridine was added as an additive based on the results reported above.
However, the amount of bismuth triflate used was 1 mole %, the amount of ligand
1a was 3 mole %, the amount of 2,2'-bipyridine was 5 mole %, and the solvent had
a water/DME volume ratio of 1/4. In addition, the reaction time was changed according
to the substrates.
The results obtained are shown in Tables 6 and 7. The symbols
in the table have the same significance described in Table 1.
[Table 6]
Experimental Example
silicon enolate
time (h)
yield (%)
ee (%)
45
21
93
91
46
70
79
92
47
30
80
88
48
34
87
89
49
22
59
92
50
9
89
88
[Table 7]
Experimental Example
silicon enolate
time (h)
yield (%)
ee (%)
51
22
81
95
52
22
68
93
53
20
66
77
54
48
79
92
55
20
82
79
Based on the results reported in Tables 6 and 7, this asymmetric
reaction system was demonstrated to be effective with various substrates.