High trans selectivity in the copper bis(oxazoline)-catalyzed asymmetric cyclopropanation of olefins by (trimethylsilyl)diazomethane

Article abstract of DOI:10.1016/j.tetlet.2003.10.068

Copper(I) bis(oxazoline) species are among the most enantioselective cyclopropanation catalysts that have been reported, although these catalysts generally give low diastereoselectivities. We have observed greatly improved diastereoselectivities using (tr

Full text of DOI:10.1016/j.tetlet.2003.10.068

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9287–9290
High trans selectivity in the copper bis(oxazoline)-catalyzed
asymmetric cyclopropanation of olefins by
(trimethylsilyl)diazomethane
Marcia B. France,* Allyn K. Milojevich, Tracy A. Stitt and Angela J. Kim
Department of Chemistry, Washington and Lee University, Lexington, VA 24450, USA
Received 12 August 2003; revised 21 September 2003; accepted 13 October 2003
Abstract—Copper(I) bis(oxazoline) species are among the most enantioselective cyclopropanation catalysts that have been
reported, although these catalysts generally give low diastereoselectivities. We have observed greatly improved diastereoselectivi-
ties using (trimethylsilyl)diazomethane as the carbon source. We have also identified several bis(oxazoline) species that also give
comparable or higher enantioselectivities with (trimethylsilyl)diazomethane compared to the more readily available ethyl
diazoacetate. The application of this methodology to several olefins has been explored.
© 2003 Elsevier Ltd. All rights reserved.
Cyclopropyl groups are found in a wide variety of
synthetic and naturally occurring compounds of inter-
est.1–6 A number of catalyst systems have been devel-
oped for the asymmetric cyclopropanation of olefins.7–11
Many of these are based on the decomposition of diazo
compounds and are believed to proceed through a metal
carbenoid intermediate. These systems include copper
complexes of chiral Schiff base, bipyridine, semicorrin,
and bis(oxazoline) ligands as well as rhodium carbox-
amides and porphyrins, ruthenium pybox, and cobalt
and ruthenium salen complexes.
by increasing the bulk of the ester functionality.7,12–19
Improved diastereoselectivities have also been observed
in the rhodium(II)-catalyzed decomposition of vinyldia-
zomethanes.20 However, such diazo compounds are not
commercially available and therefore must be prepared
prior to use. Nishiyama has also reported high trans
selectivities in the asymmetric cyclopropanation of sty-
rene with ruthenium(II) pybox complexes. While the
diastereoselectivities again increase with increasing bulk
of the diazo group, even with EDA high trans/cis ratios
on the order of 10.1:1 have been observed.21 However,
these ruthenium catalysts are less active than copper
catalysts.7,21,22
The most widely studied class of diazo reagents for the
intermolecular cyclopropanation reaction is the a-dia-
zoesters. The cyclopropanation of styrene, a common
test substrate, results in the formation of four stereoiso-
mers (Eq. (1)). The use of commercially available ethyl
diazoacetate (EDA) in this reaction generally gives
diastereoselectivities less than 2:1 in favor of the trans
stereoisomer.10 Diastereoselectivities can be improved
In the course of our investigations of the asymmetric
cyclopropanation of styrene with diazo compounds
catalyzed by copper salen and diimine complexes,
we observed that the use of commercially avail-
able (trimethylsilyl)diazomethane (TMSDM) leads to
extremely high diastereoselectivities. In some cases,
(1)
Keywords: cyclopropanation; diazo compounds; enantioselection; diastereoselection.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.068

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M. B. France et al. / Tetrahedron Letters 44 (2003) 9287–9290
only trace amounts of the cis isomer could be detected
by GC. To our knowledge, relatively few examples of
cyclopropanations with TMSDM have been reported.
One of the earliest reports involved an achiral copper
system, in which a trans/cis ratio of 9.3:1 was observed
for the cyclopropanation of cyclohexene.23 The few
systems that have been reported reveal that trans iso-
mers are strongly favored in the copper-catalyzed
cases,24–26 but no one has thoroughly explored this
phenomenon. While our salen and diimine systems gave
only low to moderate enantioselectivities, the observa-
tion of high diastereoselectivities led us to investigate
whether such a strong preference for the trans isomer
would also be observed in reactions using other catalyst
systems previously known to give high enantio-
selectivities.
such reactions,28 it was found to be less effective than
[Cu(CH3CN)4]PF6, giving lower enantio- and
diastereoselectivities with ligands 1, 2 and 9. The results
for ligands 1, 2 and 9 are shown in Table 1. Interest-
ingly, while ligand 4 is known to give the best results
for the asymmetric cyclopropanation of styrene with
EDA as the diazo compound, it did not give the best
results when TMSDM was used as the diazo species.
For comparison purposes, the results for reactions with
ligand 4 are also included in Table 1. Many important
variables affect enantio- and diastereoselectivities, such
as the time allowed for metal ligand complexation,
addition time differences, substrate catalyst loading,
and solvent, making direct comparison of results from
different laboratories difficult.9 In our hands, the enan-
tioselectivities observed with ligand 4 were slightly
lower than those reported previously,16 but diastereo-
selectivities were comparable. The data in Table 1 thus
provide a reference for the enantio- and diastereoselec-
tivities obtained under the reaction conditions
employed in this study.
A variety of commercially available compounds was
tested in the cyclopropanation of styrene with EDA
and TMSDM in CH2Cl2 at room temperature.27 These
included copper complexes of bis(oxazoline) ligands 1–9
and semicorrin ligand 10 as well as Doyle’s dirhodium
catalyst Rh2(4S-MEOX)4 (MEOX=methyl 2-oxooxa-
zolidine-4-carboxylate), and Davies’ dirhodium com-
plex Rh2(S-TBSP)4 (TBSP=N-p-tert-butylbenzene-
sulfonyl prolinate). While the rhodium complexes
showed a slightly increased preference for the trans
isomer with TMSDM over EDA, diastereoselectivities
were only on the order of 2.5. Under our conditions,
reaction of ligand 8 with [(p-cymene)RuCl2]2 (Nishiya-
ma’s system)22 gave improved yield with TMSDM, but
lower diastereo- and enantioselectivities than EDA did.
However, all copper complexes showed improved trans
diastereoselectivities with the use of TMSDM over
EDA, and several gave such a strong preference for the
trans product that only trace amounts of the cis isomer
could be detected by GC on a chiral column.
The absolute configurations for the products derived
from EDA and ligands 1, (S,S)-2, 3, 4, 7, and 9
correlate with those reported in the literature.16,17 The
enantiomeric preference is not affected by the choice of
copper catalyst precursor. The absolute configurations
for the products derived from TMSDM have not been
determined. However, in each case, these ligands all
favored the enantiomer that came out in the opposite
elution order as the EDA analogue did. This might be
due to a preference for the opposite enantiomer or it
might be due to a difference in the elution order of the
(trimethylsilyl)cyclopropane stereoisomers relative to
the ester-functionalized cyclopropanes. As would be
expected, ligands (R,R)-2, 5, and 6 showed a preference
for the opposite enantiomer in all cases. Due to low
enantioselectivities in some or all cases, trends with
ligands 8 and 10 could not be determined.
Of the copper compounds studied, the best results were
obtained for ligands 1, 2 and 9 using [Cu(CH3CN)4]PF6
as the catalyst precursor. In fact, these ligands not only
gave improved diastereoselectivities with TMSDM but
they also gave comparable or higher enantioselectivities
to those obtained with EDA. In addition, despite the
widespread use of CuOTf as a catalyst precursor in
In order to study the effect of substrate in these reac-
tions, a variety of substituted styrenes was tested in the
reaction with ligands 2 and 9 using [Cu(CH3CN)4]PF6.
The results are presented in Table 2. In general, these
again showed high diastereoselectivities and good to

M. B. France et al. / Tetrahedron Letters 44 (2003) 9287–9290
9289
Table 1. Cyclopropanation of styrene with TMSDM and CuOTf or [Cu(CH3CN)4]PF6 in the presence of various ligands
Ligand
Metal
Diazo
Yielda
trans/cis
%ee cisb
%ee transb
Major cisc
Major transc
1
1
1
1
CuOTf
CuOTf
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
CuOTf
EDA
TMSDM
EDA
TMSDM
EDA
TMSDM
EDA
TMSDM
EDA
TMSDM
EDA
TMSDM
EDA
TMSDM
EDA
51
87
78
50
57
45
68
67
84
50
58
60
55
45
53
26
99
34
56
35
1.3
3.3
1.9
11
6
54
17
0
61
65
67
2
69
62
67
2
67
63
96
69
92
43
30
11
27
88
B
B
B
A
A
B
B
A
B
A
A
B
A
B
A
B
A
B
A
B
A
B
transd
2.5
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
4
4
4
4
9
9
9
9
57
9
56
47
54
5
54
43
91
50
86
15
40
1
A
A
A
B
B
A
B
A
B
A
B
A
B
A
B
CuOTf
3.3
2.4
29.7
2.4
6.3
2.4
30.8
2.6
23.2
2.3
9.2
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
CuOTf
CuOTf
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
CuOTf
CuOTf
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
CuOTf
CuOTf
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
TMSDM
EDA
TMSDM
EDA
1.9
5.0
1.4
31
TMSDM
transd
a Yields were determined relative to dodecane as an internal standard and are corrected by calibration with samples of known ratio.
b Product mixtures were analyzed by GC equipped with a J&W Scientific Cyclodex B column.
c Absolute configurations for the products derived from EDA correspond to that shown in Eq. (1). The absolute configurations for the products
derived from TMSDM were not determined, and the designation A or B refers to the elution order.
d Only the trans isomer was detected.
Table 2. Cyclopropanation of styrene derivatives with TMSDM and [Cu(CH3CN)4]PF6 in the presence of ligands 2 and 9
Substrate
Ligand
Yielda
trans/cis
%ee cisb,c
%ee transb
Major cisd
Major transd
Styrene
Styrene
Styrene
(R,R)-2
(S,S)-2
9
(R,R)-2
(S,S)-2
9
(R,R)-2
(S,S)-2
9
(R,R)-2
(S,S)-2
9
47
49
17
72
86
21
31
80
26
74
54
9
29.7
30.8
24.6
transe
transe
transe
30.6
39.4
14.4
19.8
22.6
8.2
47
43
>99
61
63
84
68
66
81
67
67
80
55
58
75
46
49
98
B
A
A
A
B
B
A
B
B
A
B
B
A
B
B
A
B
B
4-Bromostyrene
4-Bromostyrene
4-Bromostyrene
4-Chlorostyrene
4-Chlorostyrene
4-Chlorostyrene
4-Methylstyrene
4-Methylstyrene
4-Methylstyrene
4-Vinylanisole
4-Vinylanisole
4-Vinylanisole
61
48
25
90
38
>99
47
61
B
A
A
B
A
A
B
A
(R,R)-2
(S,S)-2
9
66
80
35
14.7
20.2
transe
a Yields were determined relative to dodecane as an internal standard and are corrected by calibration with samples of known ratio.
b Product mixtures were analyzed by GC equipped with a J&W Scientific Cyclodex B column.
c It is very difficult to obtain accurate GC integration for the cis isomers of the products formed with TMSDM since they are formed in such low
yield (all less than 5%) and the resulting GC peaks are very small.
d The absolute configurations for the products were not determined, and the designation A or B refers to the elution order.
e Only the trans isomer was detected.
high enantioselectivities. The enantiomeric preferences
paralleled the trends seen with styrene.
Acknowledgements
In conclusion, the effect of TMSDM on diastereoselec-
tivities seems to be a general phenomenon with
[Cu(CH3CN)4]PF6 as catalyst precursor. This may be
due to the steric bulk of the TMS group in analogy to
the effects seen with diazoacetates upon increasing the
steric requirements of the ester group.7,12–19
Financial Support from the American Chemical Soci-
ety-Petroleum Research Fund, Research Corporation,
and the Jeffress Memorial trust is gratefully acknowl-
edged. A.K.M., T.A.S. and A.J.K. thank Washington
and Lee University for R. E. Lee Undergraduate
Research Fellowships, and M.B.F. thanks WLU for

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M. B. France et al. / Tetrahedron Letters 44 (2003) 9287–9290
Glenn Grants. We thank Philip C. Trimmer, W. Chad-
wick Ellis, Geoffrey C. Cooper, James A. Browne, and
J. Turner Vosseller for technical assistance.
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(0.03 mmol) and metal precursor (0.015 mmol) in methyl-
ene chloride (1.5 mL) was stirred for 25 min under
nitrogen. Styrene (8.7 mmol) was added and the solution
was stirred an additional 30 min. A solution of diazo
compound (0.86 mmol) in methylene chloride (1.5 mL)
was added over 16 h using a syringe pump.
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