Catalytic asymmetric synthesis of nitrocyclopropane carboxylates

Article abstract of DOI:10.1016/j.tet.2011.05.113

A Cu(I)-catalyzed asymmetric cyclopropanation of alkenes with an iodonium ylide has been developed. The copper source, hypervalent iodine source, solvent, and additives all have a significant effect on the yields and enantioselectivities. High enantioselectivity (up to 99:1 er) and diastereoselectivity (95:5 dr trans/cis) were achieved for a wide range of alkenes. Conditions were developed to convert the trans products to the cis isomers. In addition, 1-nitrocyclopropyl carboxylates were transformed into the corresponding substituted cyclopropane amino acids and aminocyclopropanes. Moreover, a comparative study between Zn- and In-mediated reduction reactions of the nitro group in these compounds with regards to the er erosion in the process is also documented.

Full text of DOI:10.1016/j.tet.2011.05.113

Tetrahedron 68 (2012) 3487e3496
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic asymmetric synthesis of nitrocyclopropane carboxylates
*
ꢀ
Benoît Moreau, Dino Alberico, Vincent N.G. Lindsay, Andre B. Charette
ꢀ
ꢀ
ꢀ
Department of Chemistry, Universite de Montreal, PO Box 6128, Station Downtown, Montreal, QC, Canada H3C 3J7
a r t i c l e i n f o
a b s t r a c t
Article history:
A Cu(I)-catalyzed asymmetric cyclopropanation of alkenes with an iodonium ylide has been developed.
The copper source, hypervalent iodine source, solvent, and additives all have a significant effect on the
yields and enantioselectivities. High enantioselectivity (up to 99:1 er) and diastereoselectivity (95:5 dr
trans/cis) were achieved for a wide range of alkenes. Conditions were developed to convert the trans
products to the cis isomers. In addition, 1-nitrocyclopropyl carboxylates were transformed into the
corresponding substituted cyclopropane amino acids and aminocyclopropanes. Moreover, a comparative
study between Zn- and In-mediated reduction reactions of the nitro group in these compounds with
regards to the er erosion in the process is also documented.
Received 9 March 2011
Received in revised form 24 May 2011
Accepted 27 May 2011
Available online 2 June 2011
Keywords:
Asymmetric catalysis
Bis(oxazolines)
Ó 2011 Elsevier Ltd. All rights reserved.
Copper
Cyclopropanation
Nitrocyclopropane carboxylates
R
NH2
R
NO2
HO2C NH2
R
1. Introduction
R
R
Nitrocyclopropanes and nitrocyclopropane carboxylates are
important building blocks in organic chemistry and other related
sciences.1 The electron-withdrawing nature of the nitro group and
the inherent ring-strain of the cyclopropane make these com-
pounds susceptible to a number of valuable chemical trans-
formations. In particular, nucleophilic ring-openings of substituted
nitrocyclopropanes have been employed for the synthesis of amino
R2
N
O
N
R'
NH2
CO2H
R1
R3
NO2
R
O
Nu
R1
acids,2 isoxazoline N-oxides,2,3
a
-chiral amines and ethers,4 and
Fig. 1. Synthetic utility of nitrocyclopropanes.
pyrroles5 (Fig. 1). Additionally, the nitro group can be readily con-
verted into an amine allowing for the synthesis of biologically
active aminocyclopropanes6 and cyclopropane amino acids.6,7
Aminocyclopropane carboxylic acids have attracted consider-
able attention in recent years due to their potential as low molec-
ular weight inhibitors,8 for the unique properties brought by their
incorporation into peptides,9 and for their existence in several
natural products.10 Aminocyclopropane carboxylic acid (ACC)10c,d is
the simplest cyclopropane amino acid and naturally occurs in every
green plant acting as the biosynthetic precursor of the plant hor-
mone ethylene. Other naturally occurring cyclopropane amino
acids include carnosadine,10f isolated from the algae Grateloupia
carmasa, and coronatine,10g a highly potent phytotoxin produced by
Pseudomonas syringae (Fig. 2). Various synthetic cyclopropane
amino acids have important biological activities including m-tyro-
sine cyclopropane amino acid (cyclo-m-Tyr), a competitive inhibitor
of pig liver L-aromatic amino acid decarboxylase (Dopa decarbox-
ylase, DCC) against D
-m-tyrosine,11 and BILN 2061, an HCV protease
inhibitor for the treatment of Hepatitis C (Fig. 2).12
While nitrocyclopropane carboxylates have proven to be valu-
able synthetic intermediates in a number of transformations, few
methods exist for their preparation.2,3,13 Our group has reported
the synthesis of these substrates using Rh- and Cu-catalyzed
cyclopropanation reactions of either diazo or iodonium ylide de-
rivatives of nitroacetates with various alkenes (Scheme 1).14
A number of 1-nitrocyclopropane carboxylates were prepared in
good yields and diastereoselectivities, and the products were
readily converted into the corresponding aminocyclopropanes and
cyclopropane amino acids.
More recently, we examined the asymmetric Cu(I)-catalyzed
cyclopropanation of alkenes with the iodonium ylide derived from
methyl nitroacetate.15 The reaction proceeded with high enantio-
selectivity using a bis(oxazoline) ligand. We also showed that the
nitrocyclopropane carboxylate products could be converted to the
corresponding cyclopropane amino acids and aminocyclopropanes.
* Corresponding author. E-mail address: andre.charette@umontreal.ca (A.B.
Charette).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.113

3488
B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
NH2
CO2H
OH
H2N
O
O
CO2H
H2N
HN
CO2H
N
N
H2N
Ph
Ph
NH
Carnosadine
2a (6 mol %)
cyclo- -Tyr
ACC
Cu(MeCN)4PF6 (5 mol %)
Ph
CO2Me
NO2
MeO2C
NO2
PhI=O (1.1 equiv), M.S.
styrene (5 equiv)
1
OMe
3a
10%
CH2Cl2, 3 h, rt
er: 87.5 : 12.5
dr: 85 : 15
O
H
N
Scheme 2. Initial copper-catalyzed cyclopropanation reaction.
S
O
HN
H
O
N
HN
and on the yield of the desired product. While copper halides and
triflates were ineffective at carrying out this transformation,
promising results were obtained for more dissociated copper
complexes (Table 1). The difference in reactivity can be attributed to
the increased electrophilicity of the copper(I) species.16 In this
system, the reactivity as a function of the counterion follows the
trend: OTf<PF6<B(ArF)4<SbF6. The hexafluoroantimonate coun-
terion proved to be optimal, affording the product in 58% yield and
91:9 enantiomeric ratio (entry 5). Since CuSbF6 provided a superior
enantiomeric ratio compared to Cu(MeCN)4PF6 using CH2Cl2 as
solvent (entry 2 vs 5), we hypothesized that acetonitrile may have
been responsible for the drop in enantioselectivity observed with
Cu(MeCN)4PF6. Therefore, we conducted a controlled reaction us-
ing CuSbF6 in the presence of acetonitrile and, as expected, we
observed a lower enantiomeric ratio (76:24). We next examined
a variety of solvents and found that benzene and toluene were the
most effective, especially under dilute conditions (entries 10 and
11). The use of copper(II) hexafluoroantimonate led to similar
results (entry 12).
H
N
N
HO2C
CO2H
O
O
O
O
HN
BILN 2061
(+)-Coronatine
Fig. 2. Biologically active cyclopropane amino acids.
Rh or Cu
RO2C NO2
R1
RO2C
NO2
catalyst
N2
R1
RO2C NO2
R1
RO2C
NO2
PhI (III)
RO2C
NO2
IPh
iodonium ylide
Table 1
Scheme 1. Rh- and Cu-catalyzed cyclopropanation of diazo and iodonium ylide
Effect of copper source and solvent on the yield and enantioselectivity
derivatives of nitroacetates.
Herein, we report the details of our studies and disclose improved
enantiomeric ratios using an optimized bis(oxazoline) copper cat-
alyst. In addition, we show that the trans cyclopropane products can
be converted to the cis isomer, in excellent stereoselectivities.
Moreover, a comparative studyof the Zn- andIn-mediated reduction
of the nitro group is shown, revealing the crucial importance of the
nature of the metal to minimize the er erosion in the process.
Entry
Copper salta
Solvent
Yieldb
drc,d
ere
1
2
3
4
5
6
7
8
(CuOTf)2$Tol
Cu(MeCN)PF6
CuPF6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
11
15
37
58
65
72
54
36
58
73
63
d
d
92:8
92:8
90:10
92:8
92:8
93:7
91:9
95:5
92:8
93:7
93:7
87:13
nd
nd
f
2. Results and discussion
CuB(ArF)4
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
Cu(SbF6)2
CH2Cl2
91:9
Toluene
Benzene
ClC6H5
o-Xylene
Tolueneg
Benzeneh
Benzene
92.5:7.5
94.5:5.5
90.5:9.5
95:5
95.5:4.5
95.5:4.5
95:5
2.1. Reaction conditions optimization
We began our studies by examining the cyclopropanation of
styrene with an iodonium ylide using catalytic amounts of
Cu(MeCN)4PF6 and ligand 2a in the presence of molecular sieves
(Scheme 2). The ylide is easily prepared in situ (and in fewer steps
compared to the preparation of the diazo compound) by mixing
PhI]O with methyl nitroacetate (1). The mixture was stirred in
CH2Cl2 for 3 h at room temperature and resulted in nitro-
cyclopropane carboxylate 3a in 10% yield (22% conversion based on
unreacted 1) and 87.5:12.5 enantiomeric ratio. A similar enantio-
meric ratio was observed using the corresponding diazo com-
pound. A reaction was conducted in the presence of the poorly
soluble base Na2CO3, and resulted in no significant improvement in
the yield (11%), but the starting material was fully consumed.
We suspected that the low reactivity of the copper carbene was
responsible for the low yield, since both methyl nitroacetate and
iodosobenzene were consumed within 3 h. Therefore, various
copper sources were screened and it was discovered that the
counterion had a significant effect on the reactivity of the catalyst
9
10
11
12
a
Prepared from CuCl and the Na or Ag salt of the corresponding counterion.
Isolated yield.
b
c
The major diastereomer is trans.
d
e
f
Determined by 1H NMR analysis of the crude reaction mixture.
Determined by SFC on chiral stationary phase.
B(ArF)4: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
Concentration was 0.04 M.
g
h
Concentration was 0.1 M.
Other variables were examined, including carbene precursors,
additives, bases, temperature, and catalyst loadings (Table 2).
Iodosobenzene gave significantly higher yields than (diacetox-
yiodo)benzene (entries 1 vs 2). Molecular sieves were required,
since a lower yield resulted without them (entry 3). Various alkali
metal carbonate bases were screened and sodium carbonate

B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
3489
Table 2
Table 3
Variation of the carbene precursors, catalyst loading, and temperature on the yield
and enantioselectivities
Screening of bis(oxazoline) ligands 2
Entry
1
Ligand
Yielda (%)
79
Enantiomeric ratiob
Entry
Conditions
X mol %
Yielda (%)
erb
1
2
3
4
5
6
7
8
9
PhI]O, Na2CO3
5
5
5
5
5
5
5
2
1
73
9
95.5:4.5
nd
nd
95.5:4.5
95.5:4.5
nd
95:5
95.5:4.5
95.5:4.5
PhI(OAc)2, Na2CO3
PhI]O, Na2CO3, without M.S.
PhI]O, Li2CO3
95.5:4.5
89:11
25
44
65
28
25
79
52
PhI]O, K2CO3
PhI]O, Cs2CO3
PhI]O, Na2CO3, 0 ꢀC
PhI]O, Na2CO3
2
3
68
PhI]O, Na2CO3
a
Isolated yield.
Determined by SFC on chiral stationary phase.
b
<10
nd
proved to be the best (entry 1). Potassium carbonate also gave
a good yield (entry 5), while lithium and cesium carbonate were
less effective (entries 4 and 6). At lower temperatures, the enan-
tioselectivity remained the same, but the yield was much lower
(entry 7). A higher yield was obtained by lowering the catalyst
loading to 2 mol % (entry 8), while a 1 mol % catalyst loading
resulted in a lower yield (entry 9). Finally, the reaction did not
proceed at all in the absence of CuCl, AgSbF6, or bis(oxazoline) 2a.
4
56
94.5:5.5
2.2. Modulation of the bis(oxazoline) ligand: effect on
enantioselectivity
5
6
9
85:15
81:19
The asymmetric copper-catalyzed cyclopropanation of the
iodonium ylide using 2a was achieved with a wide range of sub-
strates in good to excellent enantioselectivities. The absence of
a background reaction that would lower the enantioinduction
suggested the possibility of increasing the enantioselectivity by
fine-tuning the ligand structure. Various readily available bis(ox-
azoline) ligands bearing different substituents alpha to the nitrogen
were initially tested (Table 3).17 Phenyl-substituted ligand 2a18
initially provided the best result in terms of yield (79%) and en-
antiomeric ratio (95.5:4.5). Electron-rich substituents (2b)19
resulted in lower enantioselectivity, whereas electron-poor (2c)
and more sterically hindered aryl substituents (2d)20 afforded
lower yields (entries 2e4). Bis(oxazolines) with bulky tert-butyl
groups (2e)21 also resulted in low yield and a lower enantiomeric
ratio (entry 5). The ligand with the most rigid conformation,
brought by the introduction of an indenyl substituent (2f),22
showed no improvement (entry 6).
18
7
8
62
71
90:10
94.5:5.5
9
55
79
91:9
10
96.5:3.5c
We next examined the effect of the metaleligand chelation
angle by varying the substituents at the bridging methylene (Table
3, entries 7e9). Bulky bridging substituents decrease the
N]CeCeC]N angle and the NeCueN dihedral angle, while less
hindered substituents have the opposite effect. Variation of the size
of the bridging substituents also affects chirality projection, by
changing the proximity in space of the chiral substituent with the
reaction site. Ligand 2g,23 possessing a superior chelation angle
compared to 2a, led to lower enantioselectivity (entry 7). More
sterically hindered diethyl-substituted bis(oxazoline) 2h24 also
resulted in lower enantioselectivity and yield (entry 8). Bis(ox-
azoline) 2i,25 having a greater chelation angle compared to 2a due
to restriction brought by the cyclopropane, showed no improve-
ment (entry 9). These results indicate that the optimal chelation
angle for the asymmetric induction was that offered by the two
methyl substituents in ligand 2a. Finally, bis(oxazoline) 2j26
a
Isolated yield.
Determined by SFC on chiral stationary phase.
The antipode of the product shown was obtained.
b
c
possessing a gem-dimethyl substituent at the
to oxygen afforded higher enantioselectivity and good yield for
the reaction with styrene. The introduction of substituents at the
a
position relative
a
position to the oxygen atom locks the orientation of the phenyl
group, which may be beneficial for enantioselectivity.27
2.3. Cyclopropanation of alkenes
A number of cyclopropanation reactions were conducted using
ligands 2a and 2j (Table 4). While both ligands generally gave good

3490
B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
Table 4
Scope of the asymmetric cyclopropanation reaction
Entry
Alkene
Ligand 2a
Ligand 2j
Productd
Yielda (%)
trans/cisb
94:6
erc
Yielda (%)
trans/cisb
94:6
erc
1
2
82
45
95.5:4.5
79
96.5:3.5
92:8
93:7
95.5:4.5
84:16
51
>95:5
97.5:2.5
3
71e
d
d
d
4
5
d
d
d
74
78
>95:5
>95:5
97.5:2.5
96.5:3.5
76
93:7
96:4
6
80
93:7
95.5:4.5
79
>95:5
97:3
7
8
53
74
93:7
91:9
95.5:4.5
95.5:4.5
56
75
>95:5
>95:5
97:3
97:3
9
54
95:5
96.5:3.5
55
>95:5
97:3
10
11
72
84
95:5
99:1f
95:5
d
d
d
82:18
73
81:19
96.5:3.5
12
54
95:5
92.5:7.5
52
>95:5
93.5:6.5
a
Isolated yield.
Ratio determined by 1H NMR analysis of crude mixture.
Enantiomeric ratio (er) determined by SFC or GC analysis on chiral stationary phase.
Structure shown is the major product. The antipode of the product shown was obtained with ligand 2j.
Yield obtained by NMR using an internal standard.
After recrystallization.
b
c
d
e
f

B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
3491
Table 5
yields and diastereoselectivities of the desired product, ligand 2j
gave slightly higher enantiomeric ratios compared to 2a. Avariety of
alkenes were explored including aryl and vinyl-substituted alkenes.
Various alkyl, halo, and oxygen containing substituents are tolerated
under the reaction conditions (entries 1e6). Naphthyl-substituted
nitrocyclopropane carboxylates were obtained in 56% and 75%
yields (1- and 2-, respectively) and with high enantioselectivities
(entries 7 and 8). In addition, the 2-naphthyl-substituted nitro-
cyclopropane carboxylate could be recrystallized to afford enantio-
pure material (>99:1 er) in 65% yield. The cyclopropanation of
sterically hindered 2,4,6-trimethylstyrene led to the desired product
in 55% yield and excellent enantioselectivity (entry 9) with ligand 2j.
Indene was converted to the nitrocyclopropane in excellent yield,
diastereoselectivity, and enantioselectivity (entry 10). A high
asymmetric induction was also observed with both ligands when
1,3-butadiene and 2,3-methyl-1,3-butadiene were submitted to the
reaction conditions (entries 11e12). In both cases, the second car-
bonecarbon double bond was completely unreactive after the first
cyclopropanation. One problematic substrate was 4-methoxy-
styrene, which afforded the corresponding cyclopropane in poor
enantioselectivity (entry 4). This drop in enantioselectivity is likely
due to partial racemization occurring after the cyclopropanation
step.28
ꢀ
ꢁ
Selected bond lengths (A) and angles ( ) for nitrocyclopropane 3a
Bond angles (ꢀ)
ꢁ
Bond
Bond length (A)
Bond angles
C(1)eN(111)
C(1)eC(11)
C(1)eC(2)
C(1)eC(3)
C(2)eC(3)
C(2)eC(21)
1.490
1.493
1.538
1.502
1.491
1.497
N(111)eC(1)eC(11)
N(111)eC(1)eC(2)
N(111)eC(1)eC(3)
C(11)eC(1)eC(2)
C(11)eC(1)eC(3)
C(2)eC(1)eC(3)
C(1)eC(2)eC(3)
C(1)eC(3)eC(2)
116.5
116.8
114.3
117.2
120.8
58.7
59.4
61.8
MeO2C
NO2
I
Ph
Cuꢁ2
Ph
Ph
SbF6
4
MeO2C
MeO2C
NO2
Ph
CO2Me
NO2
I
CuSbF6ꢀ2
1b
3a
2.4. Structure determination
- H2O
NO2
The trans stereochemistry of cyclopropane 3a was confirmed
unambiguously by X-ray analysis (Fig. 3).29 Selected bond lengths
and angles are given in Table 5. As expected, the N(111)eC(1)eC(11)
angle is larger (116.5ꢀ) than that of a typical tetrahedral carbon angle
(109ꢀ). The C(1)eC(3)eC(2) angle is the largest cyclopropane angle
since C(3) is substituted with less hindered groups. Moreover, the
C(1)eC(2) bond length is the largest of the three bonds that make up
the cyclopropane ring due to repulsion between the substituents on
C(1) and C(2). The absolute stereochemistry was established by
conversionofnitrocyclopropane 3a into known cyclopropane amino
ester 8 and aminocyclopropane 10 (vide infra).
1
+
PhI=O
Scheme 3. Proposed mechanism.
Various transition state models that may account for the pos-
sible stereochemical outcome of the products are illustrated in
Fig. 4. The absolute stereochemistry observed for 3a is consistent
with Model C. In this model, the stereocontrol is provided by var-
ious factors. First, by the minimization of the interactions between
the substituent of the alkene and the phenyl group of the bis(ox-
azoline). Second, similarly to the reaction with simple diazo-
acetates,30 by minimizing the interaction of the carbene
substituents (NO2 and CO2Me) and this same phenyl group of the
ligand. Since the nitro group and the methyl ester are quite similar
in size, this latter interaction does not permit to distinguish, which
of model A (leading to the cis isomer) or C (leading to the trans
isomer) should be favored. This diastereocontrol issue is thus likely
to be inherent to the nature of the carbene rather than dependent
of the chiral ligand or the metal used.14a In analogy to the corre-
sponding Rh(II)-catalyzed process, it is reasonable to think that the
increased trans-directing ability observed of the nitro group as
compared to the methyl ester may be due to a stereoelectronic
effect in the transition state, implying electron donation from the
nitro oxygen to the approaching LUMO of the alkene, thus dis-
favoring models A and D, leaving model C as an energetically fa-
vorable transition state.3a,13c,31
Fig. 3. ORTEP drawing of nitrocyclopropane carboxylate 3a.
2.5. Proposed mechanism and explanation of the
stereochemical outcome
2.6. Synthesis of cis nitrocyclopropane carboxylates
The proposed mechanism begins with the formation of the
iodonium ylide from iodosobenzene and methyl nitroacetate
(Scheme 3). The ylide reacts with the copper catalyst to form
the metal carbene intermediate 4. The carbene undergoes
cyclopropanation with an alkene resulting in the desired nitro-
cyclopropane carboxylate.
In an effort to access all possible isomers of 1-nitro-2-aryl cy-
clopropane carboxylates, we began investigating the synthesis of
enatioenriched cis cyclopropanes. Our initial approach was to
subject 3 to decarboxylation conditions, followed by deprotonation
and treatment with a carbonyl-containing electrophile, which
should approach by the less sterically hindered side (Scheme 4).

3492
B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
Table 6
Formation of cis nitrocyclopropane carboxylates via isomerization of sodium salt
O
O
O
O
N
N
N
N
Cu
E
Cu
E
Ph
Ph
Ph
Ph
NO2
NO2
SbF6
SbF6
Ph
H
H
Ph
A
B
Entry Aryl
7
6
Compound Yielda (%) Compound Yielda (%) erb
Ph
NO2
Ph
CO2Me
NO2
CO2Me
1
2
7a
7b
82
97
6ac
6b
73
70
98.8:1.2
96.9:3.1
O
O
N
O
O
N
N
N
E
Cu
Cu
Ph
Ph
Ph
Ph
E
O2N
O2N
3
4
7c
95
97
6c
50
28
96.8:3.2
95.3:4.7
SbF6
Ph
H
SbF6
H
Ph
D
C
7d
6d
Ph
NO2
Ph
CO2Me
NO2
CO2Me
5
7e
97
6e
67
97.9:2.1
Fig. 4. Possible transition state models for the cyclopropanation.
a
Isolated yield.
b
Determined by SFC on chiral stationary phase.
The antipode of the product shown was prepared.
c
Scheme 4. Initially proposed route to cis nitrocyclopropane carboxylates.
Scheme 5. Isomerization of sodium carboxylate.
The deprotonation/functionalization of various substituted nitro-
cyclopropanes has been reported with a number of electrophiles
including benzaldehyde, iodine, and D2SO4/D2O.32,33 However, at-
tempts at generating 6 using this approach were unsuccessful.
Numerous reaction conditions were examined including varying
the base, carbonyl-containing electrophile, solvent, and tempera-
ture; and in all cases the reactions resulted in either recovered
starting material or decomposition.34
We next investigated an alternative approach to cis isomer 6 via
isomerization of sodium carboxylate 7 (Table 6). The formation of 7
was readily achieved in excellent yields from enantioenriched 3,
using conditions reported by O’Bannon and Dailey.32b,35,36 The
isomerization step was carried out by stirring 7 in DMF for 12 h
under an atmosphere of CO2 in the presence of molecular sieves.
The reaction likely proceeds via loss of CO2 to form an anionic
cyclopropane species in very low concentration, and then recom-
bines with CO2 from the less hindered side (opposite to the aryl
group) (Scheme 5).35 Finally, in situ addition of dimethylsulfate
affords the desired methyl ester 6 in modest yields, while still
preserving high enantiomeric ratios37 (Table 6).38
enantioenriched cyclopropane a-amino acids, we explored differ-
ent methods for the reduction of the nitro group into an amine.
Having already established that the Zn-mediated reduction under
acidic conditions is an efficient procedure with these compounds as
racemates,6 we applied it to the enantioenriched nitrocyclopropane
carboxylate derivatives obtained from our method. To our surprise,
significant racemization was observed when Zn was used as re-
ducing agent, either with the trans or the cis nitrocyclopropane
carboxylate 3a or 6a (conditions A, Scheme 6). This implies that
during the process, the cyclopropane ring opened and closed back
after bond rotation occurred, probably due to the presence of
a radical
a- to the cyclopropane ring in one intermediate. After
extensive optimization, we determined that In was also a suitable
reducing agent for this reaction, and that the er erosion, although
still present, was kept at a reasonable amount. Moreover, the re-
duction of nitrocyclopropane 5, issued from the decarboxylation of
3a, showed the same tendency, with significantly less racemization
using In compared to Zn. It is noteworthy that the Zn-mediated
reduction did not provoke er erosion when 1,1,2,3-
tetrasubstituted nitrocyclopropane carboxylate 3j was used in-
stead of 3a, probably because a ring opening-ring closing process
can only provoke the formation of a diastereomer, rather than the
enantiomer of the product in this case (Scheme 7).
2.7. Synthesis of cyclopropane a-amino acid derivatives via
reduction of nitrocyclopropane carboxylates
In order to demonstrate that optically active nitrocyclopropane
carboxylates are suitable precursors of the biologically relevant

B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
3493
chromatography (TLC) was performed on precoated, glass-backed
silica gel (Merck 60 F254). Visualization of the developed chro-
matogram was performed by UV absorbance, aqueous cerium
molybdate, ethanolic phosphomolybdic acid, iodine, or aqueous
potassium permanganate. Flash column chromatography was per-
formed using 230e400 mesh silica (EM Science or Silicycle) of the
indicated solvent system according to standard technique. Melting
points were obtained on a Buchi melting point apparatus and are
uncorrected. Infrared spectra were taken on a PerkineElmer
Spectrum One FTIR and are reported in reciprocal centimeters
(cmꢁ1). Nuclear magnetic resonance spectra were recorded either
on a Bruker AV 300, AMX 300, AV 400, ARX 400, or DMX 600
spectrometer. Chemical shifts for 1H NMR spectra are recorded in
parts per million from tetramethylsilane with the solvent reso-
nance as the internal standard (chloroform,
d
¼7.27 ppm). Chemical
shifts for 13C NMR spectra are recorded in parts per million from
tetramethylsilane using the central peak of deuterochloroform
(d 77.00 ppm) as the internal standard. All spectra were obtained
with complete proton decoupling. Optical rotations were de-
termined with a PerkineElmer 341 polarimeter at 589 or 546 nm.
Data are reported as follows: [
a]temp, concentration (c in g/100 mL),
and solvent. High resolution mass spectra were performed by the
ꢀ
ꢀ
Centre regional de spectroscopie de masse de l’Universite de
ꢀ
Montreal. Combustion analyses were performed by the Laboratoire
ꢀ ꢀ
ꢀ
ꢀ
d’analyse elementaire de l’Universite de Montreal.
The enantioselectivities of asymmetric cyclopropanation were
determined using super-critical fluid chromatography (SFC) on
a Berger SFC Analytical instrument equipped with a diode array UV
detector. Data are reported as follows: (column type, eluent, flow
rate, rate and retention time (tR)). Unless otherwise stated, oven
temperature was 40 ꢀC. For certain substrates, the enantiose-
lectivities of asymmetric cyclopropanation were determined using
analytical gas chromatography on a HewlettePackard 5880A gas
chromatograph equipped with a spitless mode capillary injector
and a flame ionization detector. Unless otherwise noted, the in-
jector and detector temperatures were set to 250 ꢀC and hydrogen
was used as the carrier gas (63 psi).
Scheme 6. Conversion of 3a, 5, and 6a into amines via Zn- or In-mediated nitro
reduction.
Scheme 7. Conversion of 3j to the corresponding amine 11.
Unless otherwise stated, commercial reagents were used with-
out purification. Methyl nitroacetate (1), isopropylidene
bis(4-phenyl-2-oxazoline) (2a), PhI(OAc)2, AgSbF6, and all alkenes
are commercially available from Aldrich Chemical Company. Iodo-
sobenzene was prepared according to known literature pro-
cedure.39 Molecular sieves were dried in oven under reduced
pressure at 120 ꢀC for 16 h and stored in desiccator. Copper(I)
reagents, bis(oxazoline) ligands, and AgSbF6 were handled under
argon and weighed in a glove box. Analytical data for compounds
3a,40 3b,14b 3e,15 3f,15 3g,6 3h,15 3i,15 3j,14b 3k,15 3l,15 8,6 5,15 10,41 and
6a40 were consistent with literature values.
3. Conclusions
In summary, the cyclopropanation of an iodonium ylide derived
from methyl nitroacetate with a chiral copper complex afforded
trans nitrocyclopropane carboxylates in high diastereo- and
enantioselectivity for a wide range of substrates. The trans cyclo-
propanes were readily converted to the cis isomer via isomeriza-
tion of the corresponding sodium carboxylate. In addition,
a comparative study for the nitro reduction of these compounds
revealed that Indium was a suitable alternative to Zinc, in order to
minimize the er erosion in the process. This method allows for
rapid access to enantioenriched cis and trans nitrocyclopropane
carboxylates, nitrocyclopropanes, cyclopropane amino acids, and
aminocyclopropanes.
4.2. General procedure for the cyclopropanation
CuCl (1.0 mg, 0.01 mmol, 2 mol %), AgSbF6 (4.1 mg, 0.012 mmol,
2.4 mol %), and bis(oxazoline) 2 (0.012 mmol, 2.4 mol %) were
weighed in the glove box and charged together in a flask. After
removal from glove box, the vial was capped and benzene (5 mL)
was added. The solution was stirred for 1 h at room temperature,
after which styrene (2.5 mmol, 5.0 equiv) was added to the catalyst
solution. In a separate vial, PhI]O (121 mg, 0.55 mmol, 1.10 equiv),
Na2CO3 (122 mg, 1.15 mmol, 2.30 equiv), and molecular sieves
(approx. 100 mg) were charged in a vial and purged under argon for
10 min. The solids were then quickly transferred to the catalyst
solution, followed by methyl nitroacetate (1) (59.5 mg, 0.50 mmol).
The solution was stirred at room temperature for 3 h. The reaction
was quenched with water (5 mL) and organic layer was extracted
with ethyl acetate (2ꢂ10 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced
4. Experimental section
4.1. General details
All non-aqueous reactions were run under an inert atmosphere
(argon) with rigid exclusion of moisture from reagents and glass-
ware using standard techniques for manipulating air-sensitive
compounds. All glassware was stored in the oven and/or was
flame dried prior to use under an inert atmosphere of gas. Anhy-
drous solvents were obtained either by filtration through drying
columns (THF, ether, CH2Cl2, benzene, DMF, CH3CN, toluene, hex-
ane, methanol) on a GlassContour system (Irvine, CA) or by distil-
lation over sodium (chlorobenzene, o-xylene). Analytical thin-layer

3494
B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
pressure. The crude oil residue was purified by flash column
chromatography to give the pure 1-nitrocyclopropyl carboxylate 3.
Na2SO4, concentrated under vacuum, and the crude a-amino ester
was purified on silica-gel chromatography (20% EtOAc/hexanes
after treatment of SiO2 with 1:5:19 Et3N/EtOAc/hexane) to afford
the corresponding amine 8, 9 or 10. The dr was determined by NMR
analysis of the crude mixture, and the er was determined by SFC
analysis on stationary phase after benzoylation of the amine (see
8b, 9b, 10b).
4.2.1. Methyl
(1S,2R)-1-nitro-2-(3-methoxyphenyl)-cyclopropane-
20
carboxylate (3d). Colorless oil; Rf¼0.20 (10% EtOAc in hexane); [
a]
D
þ44.2 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 7.25e7.21 (t,
J¼8.1 Hz, 1H), 6.85e6.82 (dd, J¼8.1, 2.5 Hz, 1H), 6.78e6.76 (d, J¼7.5H,
1H), 6.75e6.74 (t, J¼2.1 Hz, 1H), 3.79 (s, 3H), 3.77e3.72 (dd, J¼10.7,
8.9 Hz, 1H), 3.55 (s, 3H), 2.45e2.41 (dd, J¼8.9, 6.6 Hz, 1H), 2.24e2.20
4.5. General procedure for the benzoylation of the crude
amine 8, 9, or 10 for er determination
(dd, J¼10.7, 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 162.4, 159.6,
133.6, 129.6, 120.5, 114.0, 113.9, 71.7, 55.3, 53.2, 34.1, 21.1; IR (neat)
2955, 1744, 1542, 1437, 1347, 1217, 1147 cmꢁ1. LRMS (APCI, Pos) calcd
for C12H14O5N1 (MþH)þ: 252.2 m/z. Found 252.1 m/z; SFC (OJ Chir-
acel, 1.2% MeOH, 1.2 mL/min, 150 bar), tR 8.4 min (minor enantiomer),
tR 9.5 min (major enantiomer).
4.2.2. [(1S,2R)-2-Nitrocyclopropyl]benzene (5). Nitrocyclopropane
3a (221 mg, 1.0 mmol) was dissolved in DMSO (5 mL), treated with
a solution of NaOH (40 mg, 1.0 mmol, 1.0 equiv) in water (1.6 mL)
and stirred at 80 ꢀC for 2 h. The reaction was quenched with satu-
rated aqueous NH4Cl and the organic layer was extracted with
ether and washed successively with water and brine. The organic
layer was dried over anhydrous Na2SO4, filtered, and evaporated
under reduced pressure. The residue was purified over silica gel (5%
In a 100 mL round-bottomed flask equipped with a magnetic
stirring bar, the crude aminocyclopropane 8, 9, or 10 (0.145 mmol)
was dissolved in 10 mL CH2Cl2 at room temperature. DIPEA
(32.8
(20.2
m
m
L, 0.188 mmol, 1.3 equiv) was added, followed by BzCl
L, 0.174 mmol, 1.2 equiv). The resulting mixture was stirred
EtOAc in hexanes) to afford 5 as a colorless oil. Rf¼0.37 (5% AcOEt/
20
hexane); [
d
a]
ꢁ312 (c 1, CH2Cl2); 1H NMR (300 MHz, CDCl3)
overnight (16 h) and quenched with 10 mL aqueous saturated
NaHCO3. The phases were separated and the aqueous layer was
extracted with 2ꢂ CH2Cl2. Combined organic layers were dried
over Na2SO4 and concentrated under vacuum. The resulting residue
was purified by silica-gel chromatography using 20e35% EtOAc in
hexane elution gradient to afford the pure N-Bz-amines 8b,42,43
9b,42 or 10b44 as white solids, which spectral analysis were consis-
tent with literature values. The er was determined by SFC analysis
on stationary phase:
D
7.36e7.27 (m, 3H), 7.14e7.12 (m, 2H), 4.44e4.40 (ddd, J¼7.2, 3.9,
3.1 Hz, 1H), 3.17e3.11 (ddd, J¼10.6, 7.9, 3.1 Hz, 1H), 2.28e2.22 (ddd,
J¼10.6, 6.3, 3.9 Hz, 1H), 1.71e1.66 (ddd, J¼7.9, 7.2, 6.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 136.8, 129.3, 128.2, 127.1, 62.1, 29.9, 19.2; IR
(neat) 1540, 1499, 1362 cmꢁ1; HRMS (IE) calcd for C9H10NO2
(MþH)þ: 164.07060 m/z. Found 164.06997 m/z; SFC (OJ Chiracel, 1%
MeOH, 1 mL/min, 200 bar), tR 11.17 min (major enantiomer), tR
10.0 min (minor enantiomer).
Compound 8b: Chiralpak AD-H 25 cm, 15% i-PrOH, 3 mL/min,
35 ꢀC, 150 bar, 220 nm, tR (major) 9.2 min, tR (minor) 11.2 min
(92.5:7.5 er with conditions A, 95:5 er with conditions B, from 96:4
er for 3a).
4.3. General procedure for the zinc mediated reduction of the
nitro group to an amine (conditions A)
To nitrocyclopropane 3, 5 or 6 (1 mmol) in i-PrOH (20 mL) was
added a 1 M aqueous HCl solution (10 mmol), followed by Zn
powder (20 mmol). The solution was stirred at room temperature
for 2 h. The reaction was quenched by the addition of saturated
aqueous NaHCO3. The solution was stirred vigorously for 20 min
and then filtered through Celite. The organic layer was extracted
with CH2Cl2 (3ꢂ), dried over Na2SO4, filtered, and evaporated under
reduced pressure. The oil residue was then purified by flash column
chromatography (20% EtOAc/hexanes after treatment of SiO2 with
1:5:19 Et3N/EtOAc/hexane) to afford the corresponding amine 8, 9
or 10. The dr was determined by NMR analysis of the crude mixture,
and the er was determined by SFC analysis on stationary phase after
benzoylation of the amine (see 8b, 9b, 10b).
Compound 9b: Chiralpak AD-H 25 cm, 15% i-PrOH, 3 mL/min,
35 ꢀC, 150 bar, 220 nm, tR (minor) 5.4 min, tR (major) 6.0 min
(91.5:8.5 er with conditions A, 97:3 er with conditions B, from
>99.5:0.5 er for 6a).
Compound 10b: Chiralpak AD-H 25 cm, 15% i-PrOH, 3 mL/min,
35 ꢀC, 150 bar, 220 nm, tR (minor) 9.5 min, tR (major) 13.7 min
(91.5:8.5 er with conditions A, 95:5 er with conditions B, from 99:1
er for 5).
4.5.1. Methyl (1R,2S)-1-amino-2-phenylcyclopropanecarboxylate
(8). The general procedure for the Zn-mediated or In-mediated
reduction of nitro to amine was followed (conditions A or B).
Starting with 3a (110 mg, 0.5 mmol), the crude mixture was puri-
fied by flash column chromatography (20% EtOAc/hexanes after
treatment of SiO2 with 1:5:19 Et3N/EtOAc/hexane) to afford the
4.4. General procedure for the indium mediated reduction of
the nitro group to an amine (conditions B)
known cyclopropane derivative 8 as a as a white solid (79% yield
20
D
with conditions A, 73% yield with conditions B). [
CH2Cl2) (for 92.5:7.5 er).
a]
ꢁ73 (c 1.5,
In a 100 mL round-bottomed flask equipped with a magnetic
stirring bar, nitrocyclopropane 3, 5, or 6 (0.50 mmol) was dissolved
in 7.8 mL THF at room temperature, aqueous HCl 2 N was added
(9.0 mL, 18.0 mmol, 36 equiv) followed by In powder (1.15 g,
10.0 mmol, 20.0 equiv) in one portion. The gray heterogeneous
solution rapidly became clear and a metallic precipitate appeared.
The resulting solution was stirred at room temperature for 15 min
before 60 mL of saturated NaHCO3(aq) and 20 mL CH2Cl2 were
added slowly. The resulting mixture was stirred for 10 more min-
utes, the phases were separated and the aqueous layer was
extracted with 3ꢂ CH2Cl2. Combined organic layers were dried over
4.5.2. Methyl
(1R1aS6aS)-1-amino-1,1a,6,6a-tetrahydrocyclopro-
pana[a]indene-1-carboxylate (11). The general procedure for the
Zn-mediated reduction of nitro to amine was followed. Starting
with 3j (87 mg, 0.37 mmol) the crude oil was purified by flash
column chromatography (20% AcOEt/hexane) to afford 11 as a yel-
low oil (66 mg, 76%, 97.5% ee). Rf 0.20 (20% ethyl acetate in hexane)
[
a
]
20 ꢁ242 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 7.29e7.27 (dd,
D
J¼4.3, 1.7 Hz, 1H), 7.12e7.11 (m, 3H), 3.35 (s, 3H), 3.34e3.30 (dd,
J¼17.3, 0.9 Hz, 1H), 3.25e3.19 (dd, J¼17.3, 6.9 Hz, 1H), 2.90e2.88 (d,

B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
3495
J¼6.8 Hz, 1H), 2.30e2.26 (ddd, J¼6.9, 6.8, 0.9 Hz, 1H), 2.20e1.85 (b,
2H); 13C NMR (100 MHz, CDCl3)
171.4, 144.8, 139.4, 126.1, 125.7,
by flash column chromatography using 10% EtOAc/hexanes to af-
d
ford 6b as a white solid (45 mg, 70%, 96.9:3.1 er). Mp¼64e66 ꢀC;
20
124.3, 123.5, 51.1, 44.1, 41.6, 33.0, 32.8; IR (neat) 3375, 1725, 1305,
1130 cmꢁ1. LRMS (APCI, Pos) calcd for C12H13O2N1 [MþH]þ: 204.2
m/z. Found 204.2 m/z; SFC (OJ Chiracel, 4% MeOH, 0.8 mL/min,
150 bar), tR 12.6 min (major enantiomer), tR 11.2 min (minor
enantiomer).
Rf¼0.24 (10% EtOAc/hexanes); [
a
]
ꢁ75.0 (c 1, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d 7.30e7.27 (m, 2H), 7.15 (m, 2H), 3.90 (s, 3H),
3.44 (t, J¼9.6 Hz, 1H), 2.64 (dd, J¼9.2, 7.1 Hz, 1H), 2.04 (dd, J¼9.9,
7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
165.8, 135.0, 130.0, 129.9,
129.1, 75.5, 54.0, 33.2, 20.3; FTIR (neat) 1741, 1542, 1496, 1437, 1358,
1294, 1152 cmꢁ1; HRMS calcd for C11H11ClNO4 (MþH)þ: 256.0371.
Found 256.0372; SFC (Chiralcel OJ, 1% MeOH, 1 mL/min, 200 bar), tR
17.0 min (major enantiomer), tR 20.7 min (minor enantiomer).
4.5.3. (1R,2S)-1-Amino-2-phenylcyclopropane (10). The general
procedure for the Zn-mediated or In-mediated reduction of nitro
into amine was followed (conditions A or B). Starting with
5 (129 mg) the crude oil was purified by column chromatography
(20% EtOAc/hexanes after treatment of SiO2 with 1:5:19 Et3N/
EtOAc/hexane) to afford the pure known compound 10 as a color-
less oil (85% yield with conditions A, 62% yield with conditions B). Rf
4.7.3. Methyl (1R,2R)-2-(4-methylphenyl)-1-nitrocyclopropane car-
boxylate (6c). The title compound was prepared by the procedure
described above using cyclopropane sodium salt ent-7c (61 mg,
0.25 mmol, 1 equiv, derived from methyl (1S,2R)-2-(4-
chlorophenyl)-1-nitrocyclopropane carboxylate (3c)) and purified
by flash column chromatography using 10% EtOAc/hexanes to af-
0.27 (5% methanol in dichloromethane) [
a]
20 ꢁ124 (c 1, CH2Cl2). Lit.
D
20
[
a]
ꢁ135.4 (c 0.81, CHCl3).
D
ford 6c as a white solid (30 mg, 50%, 96.8:3.2 er). Mp¼64e66 ꢀC;
20
4.6. General procedure for the formation of
nitrocyclopropane sodium carboxylates
Rf¼0.26 (10% EtOAc/hexanes); [
a]
ꢁ68.2 (c 1, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
7.10 (m, 4H), 3.89 (s, 3H), 3.45 (t, J¼9.6 Hz, 1H),
2.66 (dd, J¼9.2, 6.9 Hz, 1H), 2.31 (s, 3H), 2.02 (dd, J¼9.9, 6.9 Hz, 1H);
To a flask was added trans nitrocyclopropane carboxylate
3 (1 equiv), absolute ethanol (1 mL/mmol), and NaOH (1 M in
ethanol, 1 equiv). The mixture was stirred for 2 h at room temper-
ature. The suspension was concentrated to dryness under reduced
pressure and dried under vacuum for 1 h. To the crude material was
triturated in CH2Cl2, filtered and dried under vacuum over 18 h to
give the corresponding sodium salt 7, which was used without
further purification in the next step. Note that the sodium salts
7aee are either insoluble or readily decarboxylated in deuterated
solvents, and therefore were not characterized by NMR.
13C NMR (100 MHz, CDCl3)
d
166.1, 138.8, 129.6, 128.4, 128.3, 72.8,
53.9, 34.0, 21.3, 20.3; FTIR (neat) 1741, 1542, 1519, 1437, 1359, 1293,
1152 cmꢁ1; HRMS calcd for C12H14NO4 (MþH)þ: 236.0917. Found
236.0916; SFC (Chiralcel OJ, 5% MeOH, 1 mL/min, 200 bar), tR
6.6 min (major enantiomer), tR 8.4 min (minor enantiomer).
4.7.4. Methyl (1R,2R)-2-(1-naphthyl)-1-nitrocyclopropane carboxyl-
ate (6d). The title compound was prepared by the procedure de-
scribed above using cyclopropane sodium salt ent-7d (56 mg,
0.20 mmol, 1 equiv, derived from methyl (1S,2R)-2-(1-naphthyl)-1-
nitrocyclopropane carboxylate (3d)) and purified by flash column
chromatography using 10% EtOAc/hexanes to afford 6d as a white
4.7. General procedure for the formation of cis
nitrocyclopropane carboxylates via isomerization of sodium
salt
solid (15 mg, 28%, 95.3:4.7 er). Mp¼113e115 ꢀC; Rf¼0.22 (10%
20
EtOAc/hexanes); [
a
]
þ161.7 (c 1, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
8.10 (d, J¼8.3 Hz, 1H), 7.84 (t, J¼8.7 Hz, 2H), 7.60e7.50 (m,
To a flask were added nitrocyclopropane sodium carboxylate
7 (0.25 mmol) and molecular sieves. The flask was purged with CO2
(g). Dimethylformamide (5 mL), which had been purged with CO2
(g) for 10 min, was added. The mixture was purged with CO2 (g) for
1 min followed by purging the headspace for 2 min. The reaction
was stirred under a balloon of CO2 for 12 h. Dimethyl sulfonate
(1.2 equiv) was added and the mixture was stirred for 45 min. The
reaction was quenched with water (5 mL) and diluted with diethyl
ether (5 mL). The aqueous layer was extracted with ether (3ꢂ5 mL).
The combined organics were dried over MgSO4, filtered, and con-
centrated to dryness under reduced pressure to give the crude
product that was purified by column chromatography.
2H), 7.42e7.33 (m, 2H), 3.99 (t, J¼10.7 Hz, 1H), 3.99 (s, 3H), 2.95 (t,
J¼7.1 Hz,1H), 2.14 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 166.1,133.8,
132.8, 129.8, 128.8, 127.5, 127.0, 126.5, 126.2, 125.2, 123.7, 72.3, 54.1,
32.1, 19.8; FTIR (neat) 1739, 1541, 1509, 1436, 1355, 1296, 1152 cmꢁ1
;
HRMS calcd for C15H14NO4 (MþH)þ: 272.0917. Found 272.0919; SFC
(Chiralcel OJ, 10% MeOH, 1 mL/min, 200 bar), tR 13.0 min (major
enantiomer), tR 30.2 min (minor enantiomer).
4.7.5. Methyl (1R,2R)-2-(2-naphthyl)-1-nitrocyclopropane carboxyl-
ate (6e). The title compound was prepared by the procedure de-
scribed above using cyclopropane sodium salt ent-7e (56 mg,
0.20 mmol, 1 equiv, derived from methyl (1S,2R)-2-(2-naphthyl)-1-
nitrocyclopropane carboxylate (3e)) and purified by flash column
chromatography using 10% EtOAc/hexanes to afford 6e as a beige
4.7.1. Methyl (1S,2S)-1-nitro-2-phenylcyclopropanecarboxylate
(6a). The title compound was prepared by the procedure de-
scribed above using cyclopropane sodium salt ent-7a (50 mg,
0.22 mmol, 1 equiv, derived from methyl (1R,2S)-1-nitro-2-
phenylcyclopropanecarboxylate (3a)) and purified by flash col-
umn chromatography using 10% EtOAc/hexanes to afford 6a as
solid (35 mg, 67%, 97.9:2.1 er). Mp¼79e81 ꢀC; Rf¼0.26 (10% EtOAc/
20
hexanes); [
d
a
]
ꢁ129.7 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3)
D
7.82e7.78 (m, 3H), 7.67 (br s, 1H), 7.48 (m, 2H), 7.34 (dd, J¼8.5,
1.7 Hz, 1H), 3.92 (s, 3H), 3.64 (t, J¼9.5 Hz, 1H), 2.83 (dd, J¼9.2,
7.0 Hz, 1H), 2.12 (dd, J¼9.8, 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
a white solid (35 mg, 73%, 98.8:1.2 er). Rf¼0.41 (10% EtOAc/hex-
d 166.0, 133.4, 133.2, 128.9, 128.7, 128.1, 127.9, 127.6, 126.7, 126.6,
20
anes); [
a
]
þ70.9 (c 1, CH2Cl2); SFC (Chiralcel OJ, 5% MeOH, 1 mL/
126.2, 72.8, 54.0, 34.2, 20.4; FTIR (neat) 1739, 1540,1509, 1437, 1359,
1292, 1151 cmꢁ1; HRMS calcd for C15H14NO4 (MþH)þ: 272.0917.
Found 272.0919; SFC (Chiralcel OJ, 10% MeOH, 1 mL/min, 200 bar),
tR 16.6 min (major enantiomer), tR 20.3 min (minor enantiomer).
D
min, 200 bar), tR 5.6 min (minor enantiomer), tR 9.9 min (major
enantiomer). The spectral data for this compound are in agreement
with that reported in the literature.39
4.7.2. Methyl (1R,2R)-2-(4-chlorophenyl)-1-nitrocyclopropane car-
boxylate (6b). The title compound was prepared by the procedure
described above using cyclopropane sodium salt ent-7b (66 mg,
0.25 mmol, 1 equiv, derived from methyl (1S,2R)-2-(4-
chlorophenyl)-1-nitrocyclopropane carboxylate (3b)) and purified
Acknowledgements
This work was supported by the Natural Science and Engi-
neering Research Council of Canada (NSERC), the Canada Foun-
dation for Innovation, the Canada Research Chair Program and

3496
B. Moreau et al. / Tetrahedron 68 (2012) 3487e3496
16. A similar counterion effect was reported for a copper(II)-bis(oxazoline) com-
plex, see: Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller, S. J.
Angew. Chem., Int. Ed. Engl. 1995, 34, 798.
17. For reviews on bis(oxazoline) ligands: (a) Ghosh, A. K.; Mathivanan, P.; Cap-
piello, J. Tetrahedron: Asymmetry 1998, 9, 1; (b) McManus, H. A.; Guiry, P. J. Chem.
Rev. 2004, 104, 4151; (c) Desimoni, G.; Faita, G.; Jorgensen, A. Chem. Rev. 2006,
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the Universite de Montreal. B.M. is grateful to Boehringer
Ingelheim for postgraduate fellowship. V.N.G.L. is grateful to
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NSERC (PGS D) and the Universite de Montreal for postgraduate
fellowships. We are grateful to Francine Belanger-Gariepy and for
X-Ray analysis.
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