Application of a chiral copper-1,1-bis{2-[(4S)-tert-butyloxazolinyl]} cyclopropane catalyst for asymmetric cyclopropanation of styrene

Article abstract of DOI:10.1016/j.tetlet.2005.11.086

The structural effects of the bridge moiety and 5-position on bisoxazoline ligands were studied for the copper-catalyzed asymmetric cyclopropanation of styrene with ethyl diazoacetate. The 1,1-bis{2-[(4S)-tert-butyloxazolinyl]} cyclopropane ligand showed a remarkable enhancement in the stereoselectivities (trans/cis = 84/16, >99.9% ee for the trans product) compared with the previously reported best ligand, 2,2-bis{2-[(4S)-tert-butyloxazolinyl]}propane (trans/cis = 75/25, 99.0% ee for the trans product).

Full text of DOI:10.1016/j.tetlet.2005.11.086

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 523–525
Application of a chiral copper-1,1-bis{2-[(4S)-tert-butyl-
oxazolinyl]}cyclopropane catalyst for
asymmetric cyclopropanation of styrene
a,
b
*
Makoto Itagaki and Yohsuke Yamamoto
a
Organic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd, 1-98, Kasugade-naka, 3-chome,
Konohana-ku, Osaka 554-8558, Japan
b
Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan
Received 13 October 2005; revised 16 November 2005; accepted 18 November 2005
Available online 2 December 2005
Abstract—The structural effects of the bridge moiety and 5-position on bisoxazoline ligands were studied for the copper-catalyzed
asymmetric cyclopropanation of styrene with ethyl diazoacetate. The 1,1-bis{2-[(4S)-tert-butyloxazolinyl]}cyclopropane ligand
showed a remarkable enhancement in the stereoselectivities (trans/cis = 84/16, >99.9% ee for the trans product) compared with
the previously reported best ligand, 2,2-bis{2-[(4S)-tert-butyloxazolinyl]}propane (trans/cis = 75/25, 99.0% ee for the trans
product).
ꢀ
2005 Elsevier Ltd. All rights reserved.
Since NozakiÕs research group reported the first copper-
best our knowledge, no copper-catalysts, which give
higher stereoselectivities than the copper/2 catalyst,
have been disclosed for the asymmetric cyclopropana-
tion of styrene with ethyl diazoacetate. Reiser reported
a copper aza-bisoxazoline 3 catalyst for the asymmetric
cyclopropanation of styrene, but the stereoselectivities
were lower than those of the copper/2 catalyst.5
catalyzed asymmetric cyclopropanation of styrene with
1
ethyl diazoacetate in 1966, many successful catalysts
have been reported to give high trans selectivity and
2
high enantioselectivity. Copper catalysts have been very
attractive for the cyclopropanation because they are
more advantageous in regards with their price and cata-
lytic activity compared with the other metal complex
catalysts. Chiral C -symmetric bisoxazoline compounds
Meanwhile, we recently developed new efficient chiral
bis(4-aryloxazoline) ligands 4–7 (Scheme 2) with gem-di-
methyl groups at the 5-position for the copper-catalyzed
asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexa-
2
are generally well known as widely usable ligands for
asymmetric catalysis. Masamune et al. reported that a
stable crystalline Cu(II) complex catalyst 1 (Scheme 1)
to generate the active catalyst by treatment with phen-
ylhydrazine provided >90% ee for the asymmetric cyclo-
6
,7
diene with ethyl or tert-butyl diazoacetate. However,
the stereoselectivities were lower for ligands 4–7 than for
the 1–3 (Table 1). Among the series of ligands, higher
trans selectivity was observed for the cyclopropylidene-
bridged ligand 6 than the isopropylidene-bridged ligand
5 although the enantioselectivity was lower. Therefore,
we evaluated the effects of substituents at the 5-position
and at the bridge moiety on the bis[(4S)-tert-butyloxazo-
line] ligand and we have utilized these new ligands for
the copper-catalyzed asymmetric cyclopropanation of
styrene and have achieved the highest stereoselectivities
thus far. Described herein are details.
3
propanation of styrene in 1990, and subsequently,
Evans et al. demonstrated that 99% ee was achieved
using a cationic Cu(I) complex prepared in situ from
4
CuOTf and bisoxazoline 2, which is presently the most
efficient catalyst available for the asymmetric cycloprop-
anation of terminal olefins. Since EvansÕ report, to the
Keywords: Asymmetric cyclopropanation; Copper bisoxazoline cata-
lyst; Ethyl diazoacetate; Styrene.
*
Corresponding author. Tel.: +81 6 6466 5402; fax: +81 6 6466
427; e-mail: itagakim@sc.sumitomo-chem.co.jp
Bisoxazoline 8 (Scheme 3) was prepared from (S)-tert-
leucine with an adaptation of our previous reported
5
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.086

524
M. Itagaki, Y. Yamamoto / Tetrahedron Letters 47 (2006) 523–525
1
mol% Cu-catalyst
+
N CHCO R
+
2
2
R.T.
Ph
CO R
Ph
CO R
2
2
halogenated solvent
trans
cis
O
O
O
O
CuOTf
+
CuOTf
+
N
N
N
But
But
tBu
tBu
Cu
N
O
O
O
O
N
N
N
N
N
But
tBu
But
tBu
1
2
3
Masamune
Evans
Reiser
R = Et
R = Et
R = Me
Yield 80%
trans/cis = 75/25
0% ee (trans)
7% ee (cis)
Yield 77%
Yield 82%
trans/cis = 73/27
99% ee (trans)
trans/cis = 73/27
92% ee (trans)
9
7
97% ee (cis)
84% ee (cis)
Scheme 1. Previous results of the cyclopropanation of styrene with alkyl diazoacetate using 1 mol % of copper bisoxazoline catalyst.
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
But
tBu
But
tBu
8
9
4
5
Scheme 3. Structures of bisoxazoline ligands 8 and 9.
O
O
O
O
6
method. Bisoxazoline 9, which was recently prepared
by the reaction of bis[(4S)-tert-butyloxazolinyl]methane
with ethylene dibromide in the presence of n-BuLi by
Denmark and Stiff and was demonstrated to be an excel-
lent ligand for the asymmetric addition of methyllithium
N
N
N
N
MeO
OMe
6
7
1
0
to imines, was prepared using our dehydration pro-
cess of the corresponding bisamide alcohol, which
Scheme 2. Structures of recently developed bisoxazoline ligands 4–7.
6
was obtained by the reaction of (S)-tert-leucinol with
1
1
1
,1-cyclopropane dicarboxylic acid dichloride.
It
Table 1. Asymmetric cyclopropanation of styrene with ethyl diazo-
acetate (EDA)
should be noted that our method for the preparation
of 9 gave a better overall yield (49%) than that using
reported by DenmarkÕs method (29%).
8
a
b
c
Entry
Ligand
Yield (%)
Trans/cis
ee (%)
d
e
Trans
Cis
The results of the asymmetric cyclopropanation of sty-
rene with ethyl diazoacetate are shown in Table 2.
1
2
3
4
4
5
6
7
80
80
79
67
67/33
62/38
68/32
68/32
76
77
65
70
64
66
43
72
8
Although a remarkable decrease in the trans selectivity
was observed when 8 was used, it is surprising for us
that both excellent trans/cis ratio (84/16) and enantio-
selectivity (>99.9% ee) was observed with 9 because very
poor enantioselectivity (17% ee for trans isomer) were
observed with 9 in the reaction of 2,5-dimethyl-2,4-
CuOTf/ligand = 1/1.1 molar ratio, cat. 0.1 mol %, styrene/EDA = 5/1
molar ratio, 20 ꢁC, 3 h.
Based on EDA and determined by GC analysis with n-decane as the
internal standard.
Determined by GC analysis (DB-1, 30 m · 0.25 mm ID, 0.25 mm
film, column temperature 100 ꢁC).
Determined by GC analysis (Cyclodex B, 50 m · 0.25 mm ID,
a
1
2
b
hexadiene with ethyl diazoacetate. In addition, in the
reaction of 2,5-dimethyl-2,4-hexadiene with ethyl
diazoacetate similar change of substituents from isopro-
pylidene-bridge (2: trans/cis ratio = 73/27, 16% ee for
trans isomer) to cyclopropylidene-bridge (9: trans/cis
ratio = 74/26, 17% ee for trans isomer) did not improve
c
0.25 mm film, column temperature 105 ꢁC).
d
e
9
1R,2R as a major enantiomer.
9
1
R,2S as a major enantiomer.

M. Itagaki, Y. Yamamoto / Tetrahedron Letters 47 (2006) 523–525
525
Table 2. Asymmetric cyclopropanation of styrene with ethyl diazo-
acetate (EDA)
4. Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M.
M. J. Am. Chem. Soc. 1991, 113, 728.
a
b
c
5. Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045.
Entry
Ligand
Yield (%)
Trans/cis
ee (%)
6
. Itagaki, M.; Masumoto, K.; Yamamoto, Y. J. Org. Chem.
005, 70, 3292.
d
e
Trans
Cis
2
1
2
3
2
8
9
85
78
85
75/25
42/58
84/16
99
87
>99.9
99
93
>99.9
7. Itagaki, M.; Masumoto, K.; Suenobu, K.; Yamamoto, Y.
Org. Proc. Res. Develop., submitted for publication.
8. Typical experimental procedure for the cyclopropanation:
To a solution of the copper complex prepared from
CuOTf/ligand = 1/1.1 molar ratio, cat. 0.1 mol %, styrene/EDA = 5/1
molar ratio, 20 ꢁC, 3 h.
Based on EDA and determined by GC analysis with n-decane as the
internal standard.
Determined by GC analysis (DB-1, 30 m · 0.25 mm ID, 0.25 mm
film, column temperature 100 ꢁC).
Determined by GC analysis (Cyclodex B, 50 m · 0.25 mm ID,
0
.02 mmol of CuOTf (toluene)0.5, 0.022 mmol of the
ligand in 5 mL of EtOAc (anhydrous) was added
00 mmol of styrene. Ethyl diazoacetate (20 mmol) in
a
1
ethyl acetate (10 mL) was added dropwise to the solution
over a period of 3 h at 20 ꢁC, and then the mixture was
stirred at the same temperature for 12 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
temperature 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. Subsequently, the reaction
mixture was analyzed to determine the enantioselectivity
by GC (Cyclodex B, 50 m · 0.25 mm ID, 0.25 mm film,
column temperature 105 ꢁC). The absolute configurations
of the products were determined by comparison of the
order of elution from the GC of the enantiomers described
b
c
0
.25 mm film, column temperature 105 ꢁC).
d
e
9
1
R,2R as a major enantiomer.
9
1
R,2S as a major enantiomer.
the selectivities. Therefore, subtle steric and/or elec-
tronic effects of the ligand on the reactant played an
important role in these reactions. A mechanistic study
to determine the reason for the enhanced stereoselectiv-
ity by the cyclopropylidene-bridged bisoxazoline (9) in
9
in the previously reported literature.
1
3
the reaction with styrene is now underway.
9
. D-Barra, E.; Fraile, J. M.; Garc ´ı a, J. I.; G-Verdugo, E.;
Herrerias, C. I.; Luis, S. V.; Mayoral, J. A.; S-Verdu, P.;
Tolosa, J. Tetrahedron: Asymmetry 2003, 14, 773.
In conclusion, 1,1-bis{2-[(4S)-tert-butyl-2-oxazolin-
yl]}cyclopropane ligand was found to provide higher
stereoselectivities for the copper catalyzed asymmetric
cyclopropanation of styrene with ethyl diazoacetate
than that by the conventional 2,2-bis{2-[(4S)-tert-
butyl-2-oxazolinyl]}propane ligand. Applications to
various kinds of substrates for the asymmetric
cyclopropanation by the new catalyst system are in
progress.
10. Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875.
11. Preparation of 1,1-bis{2-[(4S)-tert-butyloxazolinyl]}cyclo-
0
propane (9): (S,S)-N,N -bis[2-hydroxy-tert-butylethyl]cy-
clopropane-1,3-dicarboxamide (1.38 g, 4.21 mmol), which
was readily prepared by the reaction of tert-leucinol with
cyclopropane-1,1-dicarboxylic acid dichloride in the pres-
ence of Et N and xylene (anhydrous, 70 mL) were charged
3
into a Schlenk tube and the reaction mixture was heated to
i
reflux to completely dissolve the dicarboxamide. Ti(O Pr)
4
(
120 mg, 0.421 mmol) was then added to the solution in
one portion, and the reaction mixture was refluxed for
48 h with removal of the water by-product. After the
reaction mixture was cooled to 20 ꢁC, the solution was
concentrated under reduced pressure. The resulting pale
yellow oil was purified by column chromatography
Acknowledgements
I would like to thank the Director of Sumitomo Chem-
ical Co., Ltd, Mr. H. Yamachika and the research group
manager, Dr. Y. Funaki, for their kind permission to
publish these results and their encouragement for this
work.
(
neutral alumina, hexane–AcOEt = 9:1) to give bisoxazo-
line compound 9 as a white solid, which was recrystallized
from heptane to give a white powder 9 (0.64 g, 52%). Mp:
10
7
9.5–80.2 ꢁC (lit. Mp: 79.0–80.0 ꢁC); [a]D ꢀ89.6 (c 1.09,
1
0
1
CHCl
(
3 D 3
) [lit. [a]
ꢀ83.8 (c 1.115, CHCl
): d 4.23–4.08 (m, 4H), 3.81 (dd,
J = 10.0, 7.2, 2H), 1.52–1.44 (m, 2H), 1.29–1.22 (m, 2H),
)]. H NMR
300 MHz, CDCl
3
References and notes
1
3
0
.86 (s, 18H). C NMR (75 MHz, CDCl
69.1, 33.8, 25.6, 18.2, 15.1. Anal. Calcd for C17
C, 69.83; H, 9.66; N, 9.58. Found: C, 69.3; H, 9.6; N, 9.4.
3
): d 165.4, 75.2,
1
2
. Nozaki, H.; Moriuchi, S.; Takaya, S.; Noyori, R. Tetra-
hedron Lett. 1966, 5239.
. General reviews: (a) Doyle, M. P.; McKervey, M. A.; Ye,
T. Modern Catalytic Methods for Organic Synthesis with
Diazo Compounds; John Wiley and Sons: New York, 1998;
28 2 2
H N O :
+
HRMS-ESI [MH ] Calcd for C17
Found: 293.2234.
H N O : 293.2223.
28 2 2
12. Itagaki, M.; Yamamoto, Y. Unpublished results.
13. Previously reported examples on mechanistic studies; (a)
Fraile, J. M.; Garc ´ı a, J. I.; Mart ´ı nez-Merino, V.; Mayoral,
J. A.; Salvatella, L. J. Am. Chem. Soc. 2001, 123, 7616; (b)
Østergaard, N.; Jensen, J. F.; Tanner, D. Tetrahedron
2001, 57, 6083; (c) Suenobu, K.; Itagaki, M.; Nakamura,
E. J. Am. Chem. Soc. 2004, 126, 7271.
(
1
1
b) Singh, V. K.; Gupta, A. D.; Sekar, G. Synthesis 1997,
37; (c) Doyle, M. P.; Protopopova, M. N. Tetrahedron
998, 54, 7919; (d) Lebel, H.; Marcoux, J.-F.; Molinaro,
C.; Charette, B. A. Chem. Rev. 2003, 103, 977.
. Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron
Lett. 1990, 31, 6005.
3