Practical copper-catalyzed asymmetric synthesis of chiral chrysanthemic acid esters

Article abstract of DOI:10.1021/op060238t

Practical copper salicylaldimine complex catalysts have been developed for the asymmetric synthesis of chiral chrysanthemic acid esters by the cyclopropanation reaction of 2,5-dimethyl-2,4-hexadiene with tert-butyl diazoacetate. First, the effects of the substituents on the salicylaldehyde moiety in the copper salicylaldimine complex (copper Schiff base complex) on the catalytic activity and the stereoselectivities were investigated. As a result, a substitution of hydrogen at the 5-position with the nitro group on the salicylaldehyde moiety was found to enhance the catalytic efficiency. In addtition, a combination catalyst of the copper Schiff base complex with Lewis acid was found to also enhance the catalytic efficiency and achieved 90% chemical yield and 91% ee at 20 °C with 0.1 mol % catalyst loading. Furthermore, the asymmetric induction mechanism of the cyclopropanation reaction catalyzed by the copper Schiff base complex was studied using density functional calculations.

Full text of DOI:10.1021/op060238t

Organic Process Research & Development 2007, 11, 509−518
Practical Copper-Catalyzed Asymmetric Synthesis of Chiral Chrysanthemic Acid
Esters
Makoto Itagaki*,† and Katsuhiro Suenobu‡
Organic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98, Kasugade-naka, Konohana-ku,
Osaka 554-8558, Japan, and Tsukuba Research Laboratory, Sumitomo Chemical Co., Ltd., 6, Kitahara, Tsukuba,
Ibaraki 300-3294, Japan
Abstract:
Practical copper salicylaldimine complex catalysts have been
developed for the asymmetric synthesis of chiral chrysanthemic
acid esters by the cyclopropanation reaction of 2,5-dimethyl-
2,4-hexadiene with tert-butyl diazoacetate. First, the effects of
the substituents on the salicylaldehyde moiety in the copper
salicylaldimine complex (copper Schiff base complex) on the
catalytic activity and the stereoselectivities were investigated.
As a result, a substitution of hydrogen at the 5-position with
the nitro group on the salicylaldehyde moiety was found to
enhance the catalytic efficiency. In addtition, a combination
catalyst of the copper Schiff base complex with Lewis acid was
found to also enhance the catalytic efficiency and achieved 90%
Figure 1. Examples of synthetic pyrethroids containing chry-
santhemate moiety.
chemical yield and 91% ee at 20 °C with 0.1 mol % catalyst
loading. Furthermore, the asymmetric induction mechanism of
the cyclopropanation reaction catalyzed by the copper Schiff
base complex was studied using density functional calculations.
1. Introduction
It is well-known that optically pure cyclopropane car-
boxylates show biological activities as intermediates for
insecticides or pharmaceuticals.1-4 Synthetic pyrethroids have
long been the most favored insecticides because of their high
efficacy against insect pests and their low mammalian and
environmental toxicities. Shown in Figure 1 are some
examples of synthetic pyrethroids for household use contain-
ing the chiral 3-(1-isobutenyl)-2,2-dimethylcyclopropanecar-
boxylic acid ((+)-trans-chrysanthemic acid) as the acid
moiety. Chrysanthemic acid has two chiral centers. Therefore,
there are four stereoisomers of chrysanthemic acid, and the
ester of the (+)-trans isomer generally shows the highest
insecticidal activity followed by the (+)-cis isomer, whereas
the (-)-trans and (-)-cis isomers are almost ineffective as
shown in Figure 2.5
Figure 2. A comparison of the insecticidal activity among the
four isomers of the chrysanthemate moiety.
The catalytic asymmetric cyclopropanation of alkenes
with diazoacetate is a powerful tool for the synthesis of chiral
Figure 3. Effective catalysts for the cyclopropanation of
DMHD other than the R-1648 catalyst.
* Corresponding
author.
Fax:
+81-6-6466-5427.
E-mail:
cyclopropyl esters such as chrysanthemic acid esters. Ara-
tani’s group first achieved a high ee (94%) and trans/cis ratio
(93/7) for the cyclopropanation of 2,5-dimethyl-2,4-hexadi-
ene (DMHD) with l-menthyl diazoacetate to give the
chrysanthemate catalyzed by a chiral copper salicylaldimine
complex (R-1648 shown in Scheme 1), and Aratani’s
asymmetric process has led to the successful industrial
application for the synthesis of chiral 2,2-dimethylcyclopro-
itagakim@sc.sumitomo-chem.co.jp.
† Organic Synthesis Research Laboratory, Sumitomo Chemical Co.
‡ Tsukuba Research Laboratory, Sumitomo Chemical Co.
(1) Singh, V. K.; Gupta, A. D.; Sekar, G. Synthesis 1997, 137.
(2) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919.
(3) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; John Wiley & Sons, Inc.: New
York, 1998.
(4) Aratani, T. Pure Appl. Chem. 1985, 57, 1839.
(5) Aratani, T. ComprehensiVe Asymmetric Catalysis III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Ed.; Springer-Verlag: Berlin, 2004.
10.1021/op060238t CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/23/2007
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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509

Figure 4. Structures of the copper Schiff base catalysts 1a and b, 2a and b, 3a and b.
Scheme 1. Structure of Aratani’s catalyst R-1648 and the results of the cyclopropanation of 2,5-dimethyl-2,4-hexadiene with
l-menthyl diazoacetate
pane carboxylic acid, by the asymmetric cyclopropanation
of isobutene with ethyl diazoacetate.4-7
ee for trans isomer).11 In addition, in the case of these chiral
catalysts, 1 mol % catalyst loading was too high and would
be expensive for the production of chrysanthemic acid.
Therefore, we have developed highly efficient catalysts
for the cyclopropanation of DMHD using a simple alkyl
diazoacetate such as ethyl or tert-butyl diazoacetate, which
means that the formed chrysanthemate would be easy to
convert into the chiral chrysanthemic acid as the intermediate
for pyrethroid insecticides. As a result, we recently found
two practical chiral catalysts using tert-butyl diazoacetate
to achieve >90% ee.12-14
After Aratani’s successful reports, many kinds of catalysts
for the asymmetric cyclopropanation were demonstrated.1-3,8
However, most of the alkenes used in the reports were
styrene and its derivertives. At the present time, to the best
of our knowledge, only a few reports have described the
successful asymmetric cyclopropanation of DMHD. Shown
in Figure 3 are the two highly effective catalysts for the
asymmetric cyclopropanation of DMHD, aside from Ara-
tani’s catalyst.
These are the copper bisoxazoline catalyst by Masamune9
and the copper diamine catalyst by Kanemasa.10 In all these
catalyst systems, high stereoselectivities can be achieved
using diazoacetates containing a bulky group as the ester
moiety such as l-menthyl diazoacetate or dicyclohexyl
diazoacetate with 1 mol % catalyst. However, these systems
are not industrially applicable, because the diazoacetates are
too expensive for industrial use and difficult to hydrolyze
into chrysanthemic acid from the corresponding chrysan-
themic acid ester. Meanwhile, Scott et al. reported the
asymmetric cyclopropanation of DMHD using the useful tert-
butyl diazoacetate catalyzed by the copper complexes with
biaryl Schiff base ligands, but the trans selectivity and the
enantioselectivity were moderate (trans/cis ) 75/25, 72%
In this paper, we describe several issues concerning our
development of such new catalysts for the cyclopropanation
of DMHD in our laboratory. First, we present the develop-
ment of new copper salicylaldimine complex catalysts
(copper Schiff base complex catalysts) derived from the
5-substituted salicylaldehyde with an electron-withdrawing
group. Some of these catalysts compared to unsubstituted
catalysts achieved a higher reactivity and enantioselectivity.12
Then, we present density functional studies to understand
the asymmetric induction mechanism when using these
catalysts.15 Finally, we show that the combination of such
copper Schiff base complexes with a Lewis acid further
(11) Sanders, C. J.; Gillespie, K. M.; Scott, P. Tetrahedron: Asymmetry 2001,
12, 1055.
(12) Itagaki, M.; Hagiya, K.; Kamitamari, M.; Masumoto, K.; Suenobu, K.;
Yamamoto, Y. Tetrahedron 2004, 60, 7835-7843.
(13) Itagaki, M.; Masumoto, K.; Yamamoto, Y. J. Org. Chem. 2005, 70, 3292-
3295.
(14) Itagaki, M.; Masumoto, K.; Suenobu, K; Yamamoto, Y. Org. Process Res.
DeV. 2006, 10, 245-250.
(15) Suenobu, K.; Itagaki, M.; Nakamura, E. J. Am. Chem. Soc. 2004, 126,
7271-7280.
(6) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1975, 1707.
(7) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1977, 2599.
(8) Lebel, H.; Marcoux, J-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003,
103, 977.
(9) Lowenthal, R. E.; Masamune, S. Tetrahedron Lett. 1991, 32, 7373.
(10) Kanemasa, S.; Hamura, S.; Harada, E.; Yamamoto, H. Tetrahedron Lett.
1994, 35, 7985.
510
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

Scheme 2. Synthesis of copper Schiff base complexes 1-3a
a (i) D-Alanine methyl ester hydrochloride in THF, 0 °C, 3 h, then H3O+, followed by NH4OH, 55-75%, (ii) substituted salicylaldehyde in toluene, reflux 1 h,
62-97%; (iii) copper acetate monohydrate in AcOEt, reflux, 1 h, then NaOH-H2O, 95-98%.
Table 1. Asymmetric cyclopropanation DMHD with ethyl
mononuclear copper complex that is considered to be the
active form for the cyclopropanation.4 In the order of 1a,
2a, and 3a, the enantioselectivity of the trans product was
enhanced, while the trans/cis ratio of the product was reduced
in the presence of a 0.5 mol % catalyst loading (entries 1, 5,
9). The results are consistent with those of Aratani,4 although
the presence of a nitro group on the salicylaldehyde
framework did not show a remarkable difference with the
0.5 mol % catalyst (entries 3, 7, 11). Meanwhile, all cases
with the 0.1 mol % catalysts 1a, 2a, and 3a decreased not
only in the yields but also in enantioselectivity, compared
to those with the 0.5 mol % (entries 1 vs 2, 5 vs 6, 9 vs 10).
However, almost the same yield and ee were retained in each
case with the 0.1 mol% catalysts 1b, 2b, and 3b as those
with the 0.5 mol % catalyst (entries 3 vs 4, 7 vs 8, 11 vs
12). These results clearly indicated that the copper Schiff
base catalysts derived from salicylaldehyde lose the catalytic
activity faster than those derived from 5-nitrosalicylaldehyde.
Actually, we analyzed the reaction mixture based on the
structure of the used catalyst 2a after the cyclopropanation
by HPLC. We found that not only the original copper
complex 2a but also the corresponding Schiff base ligand
did not exist in the reaction mixture any more, and an adduct
of ethyl diazoacetate with the phenol oxygen of the Schiff
base ligand was detected as shown in Scheme 3.
Therefore, in order to interrupt the attack of the diazo-
acetate on the copper-oxygen bond (Cu-O-Aryl), a methyl
or tert-butyl group was introduced at the 3-position on the
benzene ring in the salicylaldehyde moiety of the copper
complex 2. However, no enhancements of the chemical yield
and stereoselectivities (trans/cis ratio and ee) were observed.
Subsequently, several Schiff bases with various electron-
withdrawing substituents on the salicylaldehyde framework
in the copper complex 2 were examined (Figure 5). We found
that the 5-substituted copper complexes with an electron-
withdrawing group were more effective for the enantiose-
lectivity than the 3-substituted ones, except for the fluorine
substituted complex 2j as shown in Table 2.
diazoacetate (EDA)a
eee (%)
entry catalyst mol %b yieldc (%) trans/cisd transf cisg
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
2a
2a
2b
2b
3a
3a
3b
3b
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
95
80
97
96
96
83
97
96
96
82
96
95
61/39
63/37
61/39
61/39
58/42
60/40
58/42
58/42
55/45
58/42
54/46
54/46
60
32
59
58
65
40
67
65
80
44
80
78
59
30
50
48
69
39
65
60
61
39
60
56
10
11
12
a Reaction conditions: 10 mmol of EDA, 70 mmol of DMHD, 5 mL of ethyl
acetate, 0.01 mmol of the copper complex as the monomeric complex, and 0.01
mmol of phenylhydrazine, 80 °C, 2 h. b Mol % of the mononuclear complex
based on EDA. c Based on EDA and determined by GC analysis (DB-1, 30 m
× 0.25 mm ID, 0.25 mm film, column temp 100 °C) with n-decane as the internal
standard. d Determined by GC analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm
film, column temp 100 °C). e Determined by LC analysis (Sumichiral OA-2500
(25 cm × 4 mm ID, 5 µm film) × 2, UV 220 nm, n-hexane 0.7 mL/min). f 1R,3R
as a major enantiomer. g 1R,3S as a major enantiomer.
enhances the reactivity and enantioselectivity, i.e., 90% yield
and more than 90% ee when using tert-butyl diazoacetate at
20 °C with 0.1 mol % catalyst loading.12
2. Results and Discussion
2.1. Effects of Substituents of Aminoalcohol Frame-
work and Salicylaldehyde Framework on the Stereose-
lectivity and the Catalytic Efficiency. Copper Schiff base
complexes 1-3 shown in Figure 4 were synthesized from
chiral aminoalcohols, salicylaldehyde derivatives, and cop-
per(II) acetate hydrate (Scheme 2) in order to examine effects
of the substituents of aminoalcohol framework and salicy-
laldehyde framework on the stereoselectivity and the catalytic
efficiency. The results of the asymmetric cyclopropanation
of 2,5-dimethyl-2,4-hexadiene (DMHD) with ethyl diazo-
acetate (EDA) are shown in Table 1.
A comparison of the turnover numbers between 2a and
2b is shown in Figure 6. A remarkable decrease in both the
yield and ee was observed with the higher turnover numbers
As described in Aratani’s report, phenylhydrazine was
used to convert the binuclear copper complex into the
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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511

Scheme 3. Structure of the used catalyst 2a after the cyclopropanation
Table 2. Asymmetric cyclopropanation of DMHD with EDA
2.2. Effect of Temperatures on the Selectivity. At lower
using 2 as the catalysta
reaction temperatures, higher enantiomeric excesses of the
product were obtained, but the yield of the product was
lowered with catalyst 2b or 3b, as shown in Table 3.
A bulky group in the diazoacetate was reported to increase
the enantioselectivity and trans/cis ratio.4,7 When tert-butyl
diazoacetate was used, the enantiomeric excesses for the
trans product reached 91% and 93% for both catalysts 2b
and 3b at 20 °C, respectively, although the yield was low.
The trans/cis ratio was slightly better with 2b than 3b. The
slow rate of the process and the low yield of the product
could be dramatically improved by the addition of a Lewis
acid.
eee (%)
entry catalyst mol %b yieldc (%) trans/cisd transf cisg
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
83
96
97
98
97
94
97
97
96
97
60/40
58/42
59/41
60/40
58/42
60/40
58/42
58/42
60/40
59/41
40
65
55
42
65
46
63
62
43
62
39
60
48
33
58
40
57
58
41
57
10
2j
2.3. Effect of a Lewis Acid on the Selectivities. In order
to achieve a high yield and a high enantioselectivity, the
addition of an equimolar amount of a Lewis acid was
examined with 0.1 mol % catalyst 2b at 0 °C or 20 °C. The
results are shown in Table 4. It is noteworthy that the addition
of a Lewis acid increased the reaction rate, and even at 20
°C, 95% yield was obtained in the presence of Al(OEt)3 (77%
a Reaction conditions: 10 mmol of EDA, 70 mmol of DMHD, 5 mL of ethyl
acetate, 0.01 mmol of the copper complex as the monomeric complex, and 0.01
mmol of phenylhydrazine, 80 °C, 2 h. b Mol % of the mononuclear complex
based on EDA. c Based on EDA and determined by GC analysis analysis (DB-
1, 30 m × 0.25 mm ID, 0.25 mm film, column temp 100 °C) with n-decane as
the internal standard. d Determined by GC analysis (DB-1, 30 m × 0.25 mm
ID, 0.25 mm film, column temp 100 °C). e Determined by LC analysis
(Sumichiral OA-2500 (25 cm × 4 mm ID, 5 µm film) × 2, UV 220 nm, n-hexane
0.7 mL/min). f 1R,3R as a major enantiomer. g 1R,3S as a major enantiomer.
for 2a, while, in the case of catalyst 2b, the degree of
decrease in the yield and the ee is much lower than that by
2a. These results suggested that the copper Schiff base
catalyst 2b derived from the 5-substituted salicylaldehyde
with an electron-withdrawing group becomes more efficient
than the unsubstituted copper complex 2a on the salicylal-
dehyde moiety for the asymmetric cyclopropanation of
DMHD.
Figure 6. Comparison of catalytic efficiency between 2a and
2b at 80 °C.
Figure 5. Structures of the copper catalysts 2a-j.
512
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

Table 3. Influence of reaction temperature and alkyls in
diazoacetate (RDA) in the presence of 0.1 mol %a of the
catalystsb
Table 5. Effect of adding Al(OEt)3 to the copper Schiff base
catalyst on the asymmetric cyclopropanation of DMHD with
t
N2CHCO2 Bua (DATB)
eee (%)
entry catalyst RDA (°C) (%) trans/cisd transf cisg
eed (%)
R in
T
yieldc
Cu
Lewis
acid
T
yieldb
entry complex
(°C) (%) trans/cisc transe cisf
1
2
3
4
5
6
7
8
9
2b
2b
2b
2b
2b
2b
3b
3b
3b
3b
Et
Et
Et
t-Bu
t-Bu
t-Bu
Et
Et
t-Bu
t-Bu
80
20
0
80
20
0
80
0
80
20
96
58
35
88
27
6
95
56
87
11
58/42
58/42
57/43
72/28
78/22
79/21
54/46
50/50
72/28
77/23
65
75
83
83
91
93
78
82
84
93
60
70
78
55
3
64
56
67
20
23
1
2
3
4
2b
2b
3b
3b
none
Al(OEt)3 20
none
Al(OEt)
20
27
90
11
86
78/22
78/22
77/23
77/23
91
91
93
93
63
62
23
24
20
20
a Reaction conditions: 0.01 mmol of the copper complex as the monomeric
complex, 0.01 mol of Lewis acid, 10 mmol of DATB, 70 mmol of DMHD, and
5 mL of ethyl acetate. b Based on TBDA and determined by GC analysis (DB-
1, 30 m × 0.25 mm ID, 0.25 mm film, column temp 100 °C) with n-decane as
the internal standard. c Determined by GC analysis (DB-1, 30 m × 0.25 mm
ID, 0.25 mm film, column temp 100 °C). d Determined by GC analysis (DB-
210, 30 m × 0.25 mm ID, 0.25 mm film, column temp 115 °C) after
10
t
transformation into l-menthyl chrysanthemate when N2CHCO2 Bu was used.
a Mol % of monomeric complex based on RDA. b Reaction conditions: 0.01
mmol of the catalyst as the monomeric compelx, 0.01 mmol of phenylhydradine,
5 mL of ethyl acetate, 10 mmol of RDA, and 70 mmol of DMHD. c Based on
RDA and determined by GC analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm
film, column temp 100 °C) with n-decane as the internal standard. d Determined
by GC analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column temp 100
°C). e Determined by LC analysis (Sumichiral OA-2500 (25 cm × 4 mm ID, 5
µm film) × 2, UV 220 nm, n-hexane 0.7 mL/min) when N2CHCO2Et was used.
e Determined by GC analysis (DB-210, 30 m × 0.25 mm ID, 0.25 mm film,
column temp 115 °C) after transformation into l-menthyl chrysanthemate when
e 1R,3R as the major enantiomer. f 1R,3S as the major enantiomer.
also examined with EDA, and an enhancement in the yield
was observed (entry 9 vs 10).
Furthermore, when tert-butyl diazoacetate was used
instead of ethyl diazoacetate, 91% yield and 91% ee for the
trans product were obtained at 20 °C in the presence of 0.1
mol% of 2b combined with Al(OEt)3 (entry 1 vs 2, in Table
5). The use of the catalyst composed of 3b and Al(OEt)3
also achieved 86% yield and 93% ee.
N2CHCO2 Bu was used. f 1R,3R as the major enantiomer. g 1R,3S as the major
enantiomer.
t
Table 4. Asymmetric cyclopropanation of DMHD with EDA
using the new catalyst system, consistent for the copper
Schiff base complex and various Lewis acids (LAs)a
Aratani achieved a higher than 90% ee for the trans
product with 1 mol % of the chiral [(R)-N-salicylidene-2-
amino-1,1-di(2-n-octyloxy-5-tert-butylphenyl)-1-propanol] cop-
per complex (R-1648) as the catalyst in the asymmetric
cyclopropanation of DMHD with l-menthyl diazoacetate,
while Masamune reported higher than 90% ee for the trans
product with 1 mol % of the chiral copper-bisoxazoline
complex using 2,6-tert-butyl-4-methylphenyl diazocetate.
To the best of our knowledge, the achievement of greater
than 90% ee is the first case of the asymmetric cyclopro-
panation of DMHD with tert-butyl diazoacetate. It should
be noted that the formed tert-butyl chrysanthemate is easy
to hydrolyze for conversion to chrysanthemic acid by an acid
catalyst, which is the key intermediate for the synthetic
pyrethroids.
2.4. Study of the Possible Mechanism Based on Density
Functional Calculations. Aratani proposed that the original
copper(II) Schiff base complexes have a dimer structure and
that the catalytically active species is likely to be a mono-
meric copper(I) complex as shown in Figure 7.4 This copper-
(I) complex can be prepared in situ by addition of phenyl-
hydrazine. The diazo compound then reacts with the copper(I)
complex to give a copper(I)-carbene complex, which
introduces the cyclopropane product via a metallacyclobutane
intermediate as shown in Figure 7. In order to probe the
possible mechanism of the asymmetric induction catalyzed
by the copper Schiff base complex, hybrid density functional
calculations were carried out using simplified models.15,16
eed (%)
Cu
T
yieldb
entry complex
LA
none
none
HfCl4
(°C) (%) trans/cisc transe cisf
1
2
3
4
5
6
7
8
9
2b
2b
2b
2b
2b
2b
2b
2b
3b
3b
20
0
20
20
58
35
84
91
91
85
95
86
56
83
58/42
57/43
58/42
58/42
58/42
58/42
58/42
57/43
50/50
49/51
75
83
76
76
72
76
77
84
82
83
70
78
71
71
68
70
71
79
67
68
B(C6F5)4
Al(OC6F5)3 20
Ti(O-iPr)4
Al(OEt)3
Al(OEt)3
none
20
20
0
0
0
10
Al(OEt)3
a Reaction conditions: 0.01 mmol of the copper complex as the monomeric
copper complex, 0.01 mmol of phenylhydradine, 0.01 mmol of Lewis acid, 10
mmol of EDA, 70 mmol of DMHD, and 5 mL of ethyl acetate. b Based on EDA
and determined by GC analysis analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm
film, column temp 100 °C) with n-decane as the internal standard. c Determined
by GC analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column temp 100
°C). d Determined by LC analysis (Sumichiral OA-2500 (25 cm × 4 mm ID, 5
µm film) × 2, UV 220 nm, n-hexane 0.7 mL/min). e 1R,3R as the major
enantiomer. f 1R,3S as the major enantiomer.
(16) Theoretical studies for the copper-catalyzed cyclopropanation with C2-
symmetric ligands were also reported by other research groups. (a) Fraile,
J. M.; Garc´ıa, J. I.; Mart´ınez-Merino, V.; Mayoral, J. A.; Salvatella, L. J.
Am. Chem. Soc. 2001, 123, 7616-7625. (b) Rasmusen, T.; Jensen, J. F.;
Østergaard, N.; Tanner, D.; Ziegler, T.; Norrby, P.-O. Chem.sEur. J. 2002,
8, 177-184. (c) Fraile, J. M.; Garc´ıa, J. I.; Gil, M. J.; Mart´ınez-Merino,
V.; Mayoral, J. A.; Salvatella, L. Chem.sEur. J. 2004, 10, 758-765.
ee, entry 7 vs 1); the reaction smoothly proceeded at 0 °C
to produce 86% yield and 84% ee (entry 8 vs 2). The
combination of the copper complex 3b with Al(OEt)3 was
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
513

Figure 7. Aratani’s proposed mechanism.
Scheme 4. Structures of the copper(I) carbene Complex from catalyst 2b
As the details of the calculations were reported else-
where,15 the catalytic key intermediate involved in the
catalyst 2b can be the copper(I) carbene complex bearing
the intramolecular hydrogen bond between the hydrogen of
the hydroxyl group and the carbonyl oxygen of the ester
group as shown in Scheme 4.
carbonyl group relative to the stereogenic center in the
transition states (TSs) of the cyclopropanation determines
Figure 8 shows a schematic representation of the orbital
interactions that are important for determining the orientation
of the carbene carbon center.15 This carbene complex is chiral
since the plane of the sp2 carbene carbon center lies
orthogonal to the plane of the salicyaldimine. The orthogonal
nature arises from the orbital interaction between the
occupied 3dxz orbital of the copper(I) atom and the vacant
2px orbital of the carbene carbon atom. If a stereogenic center
exists in the imine side chain, the orientation of the ester
Figure 8. Orbital interactions that fix the orientation of the
carbene center and the carbonyl group (back-donation (blue)
and conjugation between the Cu-Ccarbene σ-bond and carbonyl
π-orbital (red)).
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Figure 9. Schematic representation of the transition states.
the absolute stereochemistry of the C1 carbon atom in the
cyclopropane products.
The approach of DMHD to the carbene carbon atom in
the TSs is limited to only one enantioface, which is opposite
to the imine side chain. In addition, the orientation of DMHD
is limited to be the one shown in Figure 8. Although we
could locate the TSs in an alternative conformation where
the Me2CdCH moiety is closer to the salicylaldimine ligand,
the free energies of activation for these TSs were found to
be quite higher than that for the TSs that have the conforma-
tion as described in Figure 8.
After all, the most probable TSs can be selected like those
shown in Figure 9. Our calculations showed that the
transition states are the [2 + 1] addition from DMHD to the
carbene carbon of the Cu(I)-carbene complex. The enan-
tioselectivity of the trans-chrysanthemate calculated from the
Boltzmann distribution of several TSs was in qualitative
agreement with the experimental results that the (+)-trans
(1R,3R) isomer is predominantly produced.15,17 In addition,
the trans/cis ratio was able to be explained by the steric
interaction among the isobutenyl group of DMHD and the
ester carbonyl group on the Cu(I)-carbene complex.
A comparison of the LUMO energies, which are mainly
composed of the 2p orbital of the carbene carbon, was then
performed between the unsubstituted copper carbene complex
4a and the 5-nitro-substituted carbene complex 4b in Figure
10. As a result, the LUMO energies of 4b (-2.98 eV) were
found to be lower than that of 4a (-2.57 eV).
Figure 10. Simplified carbene complexes for the calculations
of LUMO energies.
carbene carbon through the copper atom. This enhancement
should bring about a high reactivity of the Cu(I)-carbene
complex toward DMHD.
2.5. Possible Mechanism for Effects of Addition of
Lewis Acids. The effects of Lewis acids can also be
explained on the basis of the following experimental results
listed in Table 6. Although the effect of Al(OEt)3 is not
observed in 2a and 2h (entries 1 vs 2, 9 vs 10), a remarkable
enhancement of the product yield was observed at 0 °C in
2e as well as 2b (entries 3 vs 4, 5 vs 6). In the case of 2g,
a slight enhancement of the yield was observed (entry 7 vs
8).
These results suggested that Al(OEt)3 coordinates with
the oxygen atom of the nitro group on the salicylaldehyde
moiety in the copper carbene complex when using the
complex 2b and Al(OEt)3 as shown in Figure 11. In order
to examine the effects of the coordination to the nitro group,
the LUMO energy of the copper carbene complex 4b
coordinated by Al(OEt)3 was calculated. As a result, the-
LUMO energy of the carbene complex coodinated by Al-
(OEt)3 (4b-Al(OEt)3, -3.33 eV) was found to be lower than
that of the uncoordinated one (4b, -2.98 eV), which
Therefore, the introduction of the electron-withdrawing
substituents on the benzene ring of the salicylaldehyde moiety
in the copper complex enhances the electrophilicity of the
(17) Nine trasition states were obtained by the calculations in ref 15.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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515

Table 6. Effects of substituents at the 5-position on the
themic acid using an acid catalyst. Furthermore, a reasoning
for the mechanism of the asymmetric induction in the copper
Schiff base catalyzed cyclopropanation mechanism has been
provided on the basis of the density functional calculations.
salicylaldehyde group in the copper Schiff base 2 with
a
Al(OEt)3
eed (%)
trans/cisc transb cisc
Cu
Lewis
acid
yieldb
(%)
entry complex
4. Experimental Section
Unless otherwise noted, all reactions were carried out
under a nitrogen atmosphere. The optical rotations were
measured using a JASCO DIP-370. The melting points were
measured using a Mettler Toledo Type FP62. The NMR
spectra were recorded using a Bruker DPX-300NMR spec-
trometer with trimethyl silane as the internal standard (δ
value in CDCl3). Ethyl diazoacetate and tert-butyl diazo-
acetate were prepared according to literature procedure.18 The
yields were determined by GC analyses with a capillary
column for the cyclopropanation. Ee values were then
determined by LC analyses with a chiral column in the case
of ethyl chrysanthemate and by GC analyses with a capillary
column in the case of tert-butyl chrysanthemate after
transformation into the l-menthyl chrysanthemate with
SOCl2, pyridine, and l-menthol.
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2e
2e
2g
2g
2h
2h
none
Al(OEt)3
none
Al(OEt)3
none
Al(OEt)3
none
Al(OEt)3
none
Al(OEt)3
5
6
60/40
60/40
57/43
57/43
57/43
57/43
58/42
57/43
58/42
58/42
38
36
83
84
84
83
84
85
84
85
36
35
78
79
81
76
79
80
78
80
35
86
35
72
29
37
32
33
10
a Reaction conditions: 0.01 mmol of copper complex as the monomeric
complex, 0.01 mmol of phenylhydradine, 0.01 mmol of Al(OEt)3, 10 mmol of
EDA, 70 mmol of DMHD, and 5 mL of ethyl acetate, 0 °C, 3 h. b Based on
EDA and determined by GC analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm
film, column temp 100 °C) with n-decane as the internal standard. c Determined
by GC analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column temp 100
°C). d Determined by LC analysis (Sumichiral OA-2500 (25 cm × 4 mm ID, 5
µm film) × 2, UV 220 nm, n-hexane 0.7 mL/min). e 1R,3R as the major
enantiomer. f 1R,3S as the major enantiomer.
4.1. Typical Procedure for Synthesis of Aminoalcohols.
(R)-2-Amino-1,1-di(2-methoxyphenyl)-1-propanol. The
methyl ester hydrochloride of D-alanine (7.0 g, 50.1 mmol)
was added to a cooled Grignard solution derived from
o-bromoanisole (49.6 g, 265 mmol) and magnesium (6.7 g,
276 mmol) in THF at 0 °C. The mixture was stirred for 3 h
at room temparature and then added to cooled 2% hydro-
chloric acid (200 mL) at 0 °C. 150 mL of toluene were added
to the mixture, and the aqueous phase was separated. The
aqueous solution was neutralized with ammonium hydroxide,
and 150 mL of toluene were added to the mixture. The
organic phase was separated, washed with saturated brine,
dried, and concentrated. A pale yellow solid was obtained,
recrystallized from CH2Cl2-n-hexane which provided the
product as a white solid (10.8 g, 75%). [R]D ) 35.5 (c ) 1,
Figure 11. Tentative scheme for the addition of Al(OEt)3 to
the copper complex 2b.
1
CHCl3); mp 89-90 °C; H NMR (CDCl3) δ 7.66 (d, J )
1.3 Hz, 2H), 7.19-6.73 (m, 6H), 5.31 (s, 1H), 4.33 (q, J )
6.5 Hz, 1H), 3.58 (s, 3H), 3.52 (s, 3H), 1.01 (d, J ) 6.6 Hz,
3H).
reasonably explains the enhancement of the reactivity by
Lewis acids.
4.2. Typical Procedure for Synthesis of Schiff Bases.
(R)-(N-5-Nitrosalicylidene)-2-amino-1,1-diphenyl-1-pro-
panol (5b). (R)-2-Amino-1,1-di(2-methoxyphenyl)-1-pro-
panol (6.32 g, 22.0 mmol) and 5-nitrosalicylaldehyde (3.68
g, 22.0 mmol) were dissolved in toluene (40 mL), and the
mixture was refluxed for 1 h. The reaction mixture was then
cooled to room temperature, and the precipitated Schiff base
was filtered and washed with heptane/toluene () 2/1 (v/v))
to yield the pure Schiff base 5b (9.12 g, 95%) as a yellow
solid. [Anal. Found: C, 68.1%; H, 5.8%; N, 5.6%. Calcd
for C22H20N2O4‚0.5C7H8: C, 68.45%; H, 5.85%; N, 5.85%];
3. Conclusions
New copper salicylaldimine complex catalysts (copper
Schiff base complex catalysts) derived from substituted
salicylaldehydes bearing an electron-withdrawing group at
the 5-position demonstrated a greater enhancement of the
turnover number than the copper catalysts derived from the
salicylaldehyde for the asymmetric cyclopropanation of 2,5-
dimethyl-2,4-hexadiene with diazoacetate. In addition, a high
yield (90%) and high enantioselectivity (91% ee) using tert-
butyl diazoacetate were first achieved by the addition of a
Lewis acid such as Al(OEt)3 under 0.1 mol % catalyst
loading. Although the current reaction system with tert-butyl
diazoacetate lowered the trans/cis ratio compared with
l-menthyl or dicyclohexyl diazoacetate, it is more practical
for industrial production of the chiral chrysanthemate than
Aratani’s or the Masamune’s catalyst due to low loading of
the cheap copper catalysts and the use of tert-butyl diazo-
acetate. The products were easily converted into chrysan-
1
[R]D ) -131 (c ) 1, CHCl3); mp 128-130 °C; H NMR
(CDCl3) δ 8.10-8.03 (m, 3H), 7.67-7.52 (m, 2H), 7.27-
6.65 (m, 8H), 5.66 (s, 1H), 5.26 (q, J ) 6.5 Hz, 1H), 3.62
(s, 6H), 1.41 (d, J ) 6.6 Hz, 3H).
(18) (a) For ethyl diazoacetate: Organic Synthesis CollectiVe Volumes 3;
Horning, E. C., Ed.; John Wiley & Sons, Inc: New York, 1955. (b) For
tert-butyl diazoacetate: Doyle, M. P.; Bagheri, V.; Wandless, T. J.; Harn,
N. K.; Brinker, D. A.; Eagle, C. T.; Loh, K.-L. J. Am. Chem. Soc. 1990,
112, 1906-1912.
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4.3. Typical Procedure for Synthesis of the Copper
Schiff Base Complexes. The Copper Complex (2b).
General procedure: 4.90 g (11.2 mmol) of the Schiff base
2b was dissolved in 250 g of ethyl acetate, and 2.24 g (11.2
mmol) of copper acetate monohydrate were then added to
this solution. The mixture was refluxed for 1 h, and aqueous
sodium hydroxide was next added and further stirred for 30
min at room temparature. The organic layer was separated,
washed with water, dried, and concentrated in vacuo, and
5.47 g of the copper Schiff base complex were obtained as
a deep green solid. Yield 98%. The copper complex was
used without further purification. [LC-MS (positive mode);
m/z ) 997]; [R]D ) 546 (c ) 0.1%, CHCl3), mp 160-163
°C (dec).
4.4. Typical Procedure for the Cyclopropanation
Catalyzed by (2b) with Ethyl Diazoacetate. Under a
nitrogen atmosphere, 498 mg (1.0 mmol) of the copper
complex 2b were dissolved in 15 mL of ethyl acetate, and
771 g (7.0 mol) of 2,5-dimethyl-2,4-hexadiene were then
added to the solution. 100 µL (1.0 mmol) of phenylhydrazine
were added by a microsyringe, and the temparature of the
reaction mixture was then raised to 80 °C. To the mixture
solution were added 500 mL of a solution of ethyl diazo-
acetate (114 g, 1.0 mol) in ethyl acetate at a constant rate
over 2 h using a pump at 80 °C. After further stirring for 30
min at 80 °C, the reaction mixture was analyzed by GC (DB-
1, 30 m × 0.25 mm ID, 0.25 mm film, column temp 100 °C
- 10 min to 250 °C) using the internal method with n-decane
as the standard for determining the yield and trans/cis ratio
and LC (Sumichiral OA-2500 (25 cm × 4 mm ID, 5 µm
film) × 2, UV 220 nm hexane 0.7 mL/min) for determining
the enantioselectivity. The products were determined by
comparison of the LC elution order of the enantiomers with
authentic samples. Part of the reaction mixture containing
167 g of ethyl chrysanthemate (0.85 mol) was concentrated
under reduced pressure, and then ethyl chrysanthemate was
obtained as a colorless oil (152 g, purity ) 98.5% by GC,
the trans/cis ratio ) 58/42, 65% ee for trans isomer, 60%
ee for cis isomer) by distillation (107-112 °C, 13 kPa). The
NMR spectra of the obtained ethyl chrysanthemate was
identical to that reported by literature.11
4.5. Typical Procedure for the Cyclopropanation
Catalyzed by (2b)-Al(OEt)3 with tert-Butyl Diazoacetate.
Under a nitrogen atmosphere, 9.96 mg (0.020 mmol) of the
copper complex 2b and 3.24 mg (0.020 mmol) of triethoxy
aluminium were added to 5 mL of ethyl acetate, and 15.4 g
(140 mmol) of 2,5-dimethyl-2,4-hexadiene were then added
to the solution. 2 µL (0.02 mmol) of phenylhydrazine were
added by a microsyringe, and the temparature of the reaction
mixture was then set to 20 °C. A solution of tert-butyl
diazoacetate (2.82 g, 20 mmol) in 10 mL of ethyl acetate
was added dropwise to the solution at a constant rate over a
period of 3 h at 20 °C, and the mixture was then further
stirred at the same temperature for 0.5 h. The reaction
mixture was filtered through silica gel and then analyzed by
GC (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column
temp 100 °C - 10 min to 250 °C) using n-decane as an
internal standard for determining the yield and trans/cis ratio.
After concentration of the reaction mixture under reduced
pressure, a pale yellow oil containing 4.03 g of tert-butyl
chrysanthemate (18 mmol) was obtained and the NMR
spectra were identical to those reported by literature.11
Afterwards, the resulting pale yellow oil was dissolved in
50 mL of toluene. Trifluoroacetic acid (205 mg, 1.8 mmol)
was then added to the solution, and the solution was refluxed
for 3 h. After cooling the reaction mixture to 40 °C, 20 mL
of water and 20 mL of 1 N sodium hydroxide were added,
and the pH of the aqueous phase showed >12. The phases
were separated, and the pH of the aqueous phase was
adjusted to <2 with 6 N hydrochloric acid. To the aqueous
phase were added 50 mL of toluene, and the organic phase
was washed with 30 mL of water. The organic phase was
then concentrated under reduced pressure to obtain chry-
santhemic acid (colorless oil, 2.90 g, yield 96%, purity )
99.0% by GC, trans/cis ratio ) 78/22), which was analyzed
by GC (DB-210, 30 m × 0.25 mm ID, 0.25 mm film, column
temp 115 °C) after transformation into the l-menthyl chry-
santhemate with SOCl2, pyridine, and l-menthol. The NMR
spectra of the obtained chrysanthemic acid were identical to
those reported by literature.19 The absolute configurations
of the products were determined by comparison of the GC
elution order of the enantiomers with authentic samples.
(19) Bramwell, A. F.; Crombie, L.; Hennesley, P.; Pattenden, G.; Elliot, M.;
Janes, N. F. Tetrahedron 1969, 25, 1727.
(20) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(21) (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Salvador, P.; Dannenberg, J. J.; Malick, D. K.; Rabuck, A. D.; Raghava-
chari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J. A. Gaussian98, revision A.11; Gaussian, Inc.:
Pittsburgh, PA, 2001. (b) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D.
K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. Gaussian 03, revision B.04; Gaussian, Inc.: Wallingford, CT, 2004.
5. Computational Methods
The density functional studies reported here were per-
formed using the B3LYP hybrid density functional method20
implemented in the Gaussian98 and Gaussian03 programs.21
The LUMO energies shown above were calculated at the
B3LYP/6-31G(d) level. The more detailed procedure for the
calculations was reported elsewhere.15
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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517

Acknowledgment
Yamachika, and the research group manager, Dr. Y. Funaki,
for their kind permission to publish these results and their
encouragement during this study.
We thank Prof. Dr. Y. Yamamoto (Hiroshima University),
Prof. Dr. E. Nakamura (The University of Tokyo), and Dr.
T. Aratani (Sumitomo Chemical Co.) for their helpful advice
and discussions related to our work. Furthermore, M.I. thanks
the Director of Sumitomo Chemical Co., Ltd., Mr. H.
Received for review November 15, 2006.
OP060238T
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