Enantioselective copper-catalyzed cyclopropanation of styrene by means of chiral bispidine ligands

Article abstract of DOI:10.1016/j.tetasy.2007.02.024

Enantiopure C₁- and C₂-symmetric bispidine ligands have been synthesized and screened in the asymmetric copper-catalyzed cyclopropanation of styrene. In order to improve the enantiomeric excesses (ee) of the cyclopropane derivatives,

Full text of DOI:10.1016/j.tetasy.2007.02.024

Tetrahedron: Asymmetry 18 (2007) 659–663
Enantioselective copper-catalyzed cyclopropanation of styrene
by means of chiral bispidine ligands
Giordano Lesma,a,* Carlo Cattenati,a Tullio Pilati,b Alessandro Sacchettia,*
and Alessandra Silvania
aDipartimento di Chimica Organica e Industriale e Centro Interdisciplinare Studi biomolecolari e applicazioni Industriali (CISI),
`
Universita degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy
bIstituto di Scienze e Tecnologie Molecolari—CNR, Via Golgi 19, 20133 Milano, Italy
Received 9 February 2007; accepted 28 February 2007
Abstract—Enantiopure C1- and C2-symmetric bispidine ligands have been synthesized and screened in the asymmetric copper-catalyzed
cyclopropanation of styrene. In order to improve the enantiomeric excesses (ee) of the cyclopropane derivatives, the best performing
C1-symmetric diamine ligand was selected for studies on the reaction conditions. The optimized procedure allowed us to obtain up to
91% ee for the cis-cyclopropane derivative and up to 79% ee for the trans one.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
dines.10 Only a few examples11 of strongly basic diamine
C2-symmetric ligands have been reported in the cycloprop-
anation reaction and, to the best of our knowledge, only
one C1-symmetric diamine ligand12 has been reported to
give moderate results in this reaction.
The advent of catalytic methods for the controlled decom-
position of diazo compounds made the use of carbene reac-
tives a well established tool for synthetic applications.1
Carbene intermediates can be easily generated starting
from diazo alkane derivatives, in the presence of different
metals. Cu and Rh complexes have proven to be the most
effective and with general applicability.2 Among the many
transformations involving metal carbene species, one of
the most studied and exploited reaction is the addition to
olefins to afford cyclopropane derivatives. The three-
membered ring is found in a wide range of synthetic and
naturally occurring compounds and metabolites.3 Cyclo-
propanes have also been widely used as versatile synthetic
intermediates for the preparation of more functionalized
molecules.4 The development of metal complexes embody-
ing chiral ligands opened the way to the stereoselective
cyclopropanation5 of alkenes, by means of diazo com-
pounds. In the field of copper-catalyzed cyclopropanations,
after the first examples by Nozaki et al.6 and Aratani
et al.,7 many chiral ligands have been proposed. The best
results were obtained with bisimine containing C2-symmet-
ric ligands, such as semicorrins,8 bisoxazolines,9 and bipyri-
In our ongoing studies on chiral nitrogen-containing
ligands, we were interested in exploring the applicability
of molecules containing the 3,7-diazabicyclo[3.3.1]nonane
moiety 1, in copper-catalyzed stereoselective reactions.
H
N
N
H
N
H
N
H
bispidine 1
The 3,7-diazabicyclo[3.3.1]nonane framework is commonly
named bispidine and has been thoroughly studied in the
past years.13 Different bispidine derivatives have been pre-
viously described both as achiral and chiral ligands, in dif-
ferent metal catalyzed reactions.14 Herein we report on the
applications of C1- and C2-symmetric enantiopure bispi-
dines in the copper-catalyzed cyclopropanation of styrene
with the use of ethyldiazoacetate (EDA) as a source of
the carbene intermediate.
*
Corresponding authors. Tel.: +39 02 50314081; fax: +39 02 50314078;
e-mail: alessandro.sacchetti@unimi.it
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.024

660
G. Lesma et al. / Tetrahedron: Asymmetry 18 (2007) 659–663
2. Results and discussion
Ph
N
O
Synthesis of the ligands was achieved through an optimized
procedure relying on a double Mannich reaction sequence.
The bispidine ring system was made chiral by means of
proper substituents at the nitrogen, bearing a stereogenic
carbon atom. These chiral residues were introduced in
the form of enantiopure primary amines in the double
Mannich reaction step. C1-Symmetric ligand 2 was pre-
pared in a single step, starting from commercially available
1-methyl-piperidin-4-one and (R)-1-naphthalen-1-yl-ethyl-
amine, as we recently reported.14a After chromatographic
purification, bispidinone 2 was isolated in 53% yield
(Scheme 1).
O
CH2O 4 eq, AcOH
Ph
Ph
2
Ph
NH2
refluxing methanol
72%
Ph Ph
N
Ph
4
Scheme 3. Synthesis of ligand 4.
C2-Symmetric ligand 4 was synthesized in a single one-pot
multi-component reaction. Double Mannich condensation
of 1,10-diphenylacetone with (R)-1-phenylethylamine and
paraformaldehyde in refluxing methanol, cleanly afforded
the desired product, which was isolated in 72% yield after
crystallization (Scheme 3). The preservation of the enantio-
meric purity of ligands 2–4 was confirmed by chiral HPLC
analysis.16
C2-Symmetric ligand 3 was also prepared through a double
Mannich strategy, starting from (R)-1-(1-phenylethyl)-pip-
eridin-4-one15 and (R)-1-phenyl-ethylamine, as shown in
Scheme 2.
The ligands were then screened in the CuI catalyzed cylo-
propanation of styrene with ethyldiazoacetate (EDA) as
carbene generator. In a typical experimental procedure,
the chiral catalyst was first prepared by stirring the chiral
ligand (0.1 equiv) and an equimolar amount of commer-
cially available CuOTfÆ0.5PhH in dry dichloromethane
for 30 min. Styrene (5 equiv) was then added, followed by
the dropwise addition of ethyl diazoacetate (1 equiv). The
reaction mixture was then stirred for 24 h at room temper-
ature. Chromatographic separation afforded cis- and trans-
diastereoisomers, which were analyzed by chiral HPLC17
to determine the ee. The results of the screening of the
ligands are reported in Table 1.
O
N
O
NH2
CH2O 2.5 eq, HCl, AcOH
refluxing ethanol
53%
N
Me
N
Me
2
Scheme 1. Synthesis of ligand 2.
Ph
The best outcome was obtained with ligand 2, giving a 68%
global yield, with a 2:3 cis/trans ratio, as determined by 1H
NMR analysis of the crude. Using HPLC, the cis-diaste-
reoisomer showed a 41% ee and the trans-diastereoisomer
37% ee. A lower enantioselectivity was achieved with C2-
symmetric ligands 3 and 4, despite the presence of accept-
able yields.
O
N
O
CH2O 2.5 eq, HCl, AcOH
Ph
NH2
refluxing ethanol
67%
N
N
Ph
Ph
3
In order to improve the results obtained, ligand 2 was
Scheme 2. Synthesis of ligand 3.
tested under various reaction conditions. The influence of
Table 1. CuI Catalyzed asymmetric cyclopropanation of styrene
2
1
N2CH2COOEt
S R
S
S
Ph
Ph
COOEt Ph
COOEt
COOEt
CuIOTf 10 mol %
+
+
cis
trans
L* 10 mol %, CH2Cl2
5
Ph
R
S
R
R
COOEt Ph
Ligand
Yielda (%)
cis/transb
eec (%) cis
eec trans (%)
2
3
4
68
66
51
2/3
1/3
1/3
41 (1S,2R)d
17 (1S,2R)
17 (1S,2R)
37 (1S,2S)d
15 (1S,2S)
18 (1S,2S)
a Calculated on the sum of the isolated diastereoisomers after chromatographic purification.
b Determined by 1H NMR analysis on the crude.
c Determined by HPLC analysis on a chiral column. See Section 4 for details.
d The absolute configuration was determined by comparison of the [a]D sign with data reported in the lit.9c

G. Lesma et al. / Tetrahedron: Asymmetry 18 (2007) 659–663
661
Table 2. Screening of solvents in the asymmetric cyclopropanation of
styrene in the presence of ligand 2
The best performing ligand 2 was further characterized by
X-ray diffraction analysis on a single crystal, isolated after
crystallization from i-PrOH (Fig. 1). The crystal structure
reveals the presence of a boat–chair conformation, with a
boat for the N-methyl substituted piperidone ring. The
large 1-naphthyl ring system is placed in the inner part of
the 3,7-diazabicyclo moiety, thus forcing the N-methyl
piperidone ring in the boat conformation.
Solvent
Yield (%) cis/trans ee (%) trans ee (%) cis
Hexane
Toluene
THF
Benzene
Dichloroethane 55
Acetonitrile 27
12
48
8
1/1
2/3
1/1
2/3
1/3
2/3
0
0
32 (1S,2S)
0
31 (1S,2S)
38 (1S,2S)
13 (1S,2S)
30 (1S,2R)
0
35 (1S,2R)
40 (1S,2R)
18 (1S,2R)
33
the solvent was firstly investigated, as reported in Table 2.
With hexane and THF, low yields and no stereoselection
were detected, probably due to the poor solubility of the
ligand in these solvents. As toluene, benzene, and dichloro-
ethane led to results comparable to dichloromethane, this
solvent was chosen for the subsequent studies.
An important feature in cyclopropanation reactions is the
addition time of the EDA. We performed different tests
varying the addition time from 1 h to 24 h through the
use of a syringe pump. We observed that the best result
was achieved with an addition time of 20 h, affording an
ee of 67% for the cis-(1S,2R)-diastereoisomer and of 61%
for the trans-(1S,2S)-diastereoisomer. The cis/trans ratio
and the yield were influenced, by varying the time of addi-
tion of EDA. When we changed the ligand/CuI ratio, we
could observe that an excess of ligand does not affect the
ee values, while an excess of CuI causes a lowering of the
ee. This result can be easily explained by assuming that
the presence of an uncomplexed copper catalyst can per-
form a cyclopropanation reaction in a non-stereoselective
manner. We could also observe that the reduction of the
excess of styrene did not influence the overall yield. In fact,
the use of 1.25 equiv excess of styrene with respect to ethyl
diazoacetate, did not cause any change in yield or ee, with
reference to the 5 equiv excess previously used. With regard
to the ligand/CuI catalyst loading, we performed different
experiments with loadings ranging from 10 mol % to
1 mol % with respect to the EDA reagent (Fig. 1).
Figure 1. ORTEP projection of compound 2. Only one of the two
independent molecules is shown. Atomic displacement parameters at 50%
probability level (see Section 4 for details).
Bispidines and bispidinones are known to act as bidentate
chelating agents toward metal cations in a chair–chair con-
formation. In order to coordinate to the CuI atom, the N-
methyl piperidone ring of ligand 2 is required to switch from
a boat to chair conformation. The mechanism of the forma-
tion of the active catalyst is currently under investigation.
The best result was obtained with a 2.5 mol % loading of
the ligand/CuI catalyst, combined with the slow addition
of EDA (20 h through a syringe pump) and 1.25 equiv
excess of styrene. Under these conditions, a 67% overall
yield (cis/trans ratio: 1/3) for the two diastereoisomers
was achieved, with a 91% ee for the cis-(1S,2R) and a
79% ee for the trans-(1S,2S) ones. This result is summa-
rized in Scheme 4.
3. Conclusions
The screening of C1- and C2-symmetric diamine bispidine
ligands in the asymmetric cyclopropanation of styrene
R
S
Ph
Ph
COOEt
91% ee
CuIOTf 2.5 mol %
+
N2CH2COOEt
+
1.25
Ph
2 2.5 mol %,
CH2Cl2
syringe pump 20 h
S
S
COOEt
79% ee
overall yield: 68%
cis/trans ratio: 1/3
Scheme 4. Optimized conditions for the asymmetric cyclopropanation of styrene in the presence of ligand 2.

662
G. Lesma et al. / Tetrahedron: Asymmetry 18 (2007) 659–663
was performed. All ligands were easily prepared in a single
step from commercially available products. The C1-sym-
metric ligand 2 showed moderate results under the usually
referred conditions, but, after fine tuning of the reaction
conditions, the outcome was improved up to 91% ee for
the cis (1S,2R) cyclopropane derivative and to 79% ee for
the trans (1S,2S) one. Ligand 2 represents the first example
of a simple C1-symmetric diamine successfully applied in
the asymmetric cyclopropanation of styrene. Further stud-
ies on ligand 2 and its modified analogues are currently in
progress, in order to expand their applicability in other
asymmetric reactions.
and then
a
solution of (R)-1-phenyl-ethylamine
(0.380 mL, 3 mmol) and AcOH (0.171 mL, 3 mmol) in
15 mL of ethanol was added dropwise (15 min). The reac-
tion was refluxed for 6 h and then allowed to reach room
temperature overnight. After evaporation of the solvent
the residual brown oil was treated with 20 mL of 30% aq
NaOH and then extracted with CH2Cl2. The crude was
purified by flash chromatography (EtOAc/MeOH/TEA,
89:9:2) affording 700 mg of 3 (67% yield). 1H NMR
(400 MHz CDCl3)
d 7.33–7.24 (m, 10H), 3.56 (q,
J = 6.7 Hz, 2H), 2.99 (m, 4H), 2.79 (m, 4H), 2.50 (m,
2H), 1.35 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3) d 215.4 (1C), 143.4 (2C), 128.2–127.0 (10C), 62.8
(2C), 54.9 (2C), 52.9 (2C), 47.0 (2C), 18.6 (2C);
20
4. Experimental
4.1. General
½aꢀD ¼ þ4:2 (c 0.5, CHCl3); HRMS m/z calcd 348.2202.
Found: 348.2209. Anal. Calcd for C23H28N2O: C, 79.27;
H, 8.10; N, 8.04; O, 4.59. Found: C, 79.30; H, 8.07; N, 8.01.
All solvents were distilled and properly dried, when neces-
sary, prior to use. All chemicals were purchased from com-
mercial sources and used directly, unless indicated
otherwise. All reactions were monitored by thin layer chro-
matography (TLC) on precoated silica gel 60 F254
(Merck); spots were visualized with UV light or by treat-
ment with 1% aqueous KMnO4 solution. Products were
purified by flash chromatography on Merck silica gel 60
4.2.3. 1,5-Diphenyl-3,7-bis-((R)-10-phenyl-ethyl)-3,7-diaza-
bicyclo[3.3.1]nonan-9-one 4. A solution of (R)-1-phenyl-
ethylamine (6.36 mL, 0.05 mol) in 30 mL of ethanol was
cooled to 0 ꢁC with an ice bath. Acetic acid (3 mL), para-
formaldehyde (3.0 g, 0.1 mmol), and 1,10-diphenylacetone
(5.25 g, 0.025 mol) were added. The mixture was refluxed
overnight. After cooling to room temperature, the suspen-
sion was filtered affording 9.12 g of 4 (72% yield).1H NMR
1
(230–400 mesh). H and 13C NMR spectra were recorded
(400 MHz CDCl3)
d 7.32–7.15 (m, 20H), 3.80 (q,
with Bruker AC 300 (1H, 300 MHz; 13C, 75.4 MHz) and
400 MHz Avance (1H, 400 MHz; 13C, 100 MHz) NMR
spectrometers. Chemical shifts are reported in parts per
million downfield from SiMe4 (d = 0.0). HRMS spectra
were measured on a Jeol SX 102 instrument equipped with
its standard sources. Optical rotations were measured with
a Perkin–Elmer 241 polarimeter.
J = 6.8 Hz, 2H), 3.47 (br d, J = 10.7 Hz, 4H), 3.13 (br d,
J = 9.8 Hz, 2H), 3.10 (br d, J = 10.8 Hz, 2H), 1.47 (d,
J = 6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 211.5
(1C), 143.3 (2C), 142.5 (2C), 129.3–124.5 (20C), 63.2
(2C), 60.9 (2C), 58.3 (2C), 54.5 (2C), 17.8 (2C);
20
½aꢀD ¼ ꢁ8:4 (c 1, CHCl3); HRMS m/z calcd 500.2828.
Found: 500.2821. Anal. Calcd for C35H36N2O: C, 83.96;
H, 7.25; N, 5.60; O, 3.20. Found: C, 83.89; H, 7.29; N, 5.68.
4.2. Synthesis
4.2.1. (10R,1R,5S)-3-Methyl-7-(10-naphthalen-1-yl-ethyl)-3,7-
diaza-bicyclo[3.3.1]nonan-9-one 2. Compound 2 was pre-
pared according to Ref. 14a. H NMR (400 MHz CDCl3)
4.3. Optimized procedure for the cyclopropanation reaction
1
A solution of the catalyst was prepared by stirring, under
argon, the ligand (0.025 mmol) and commercially available
CuOTfÆ0.5PhH (0.025 mmol) in dry dichloromethane
(10 mL) for 30 min. Styrene (1.25 mmol) was added to
the solution. Then ethyl diazoacetate (1.0 mmol) was added
over a period of 20 h by a syringe pump. After 4 h under
stirring, the mixture was concentrated under reduced pres-
sure. The residue oil was purified by flash chromatography
with 99:1 hexane/diethyl ether as eluant to isolate the cis
and the trans diastereoisomers. The cis/trans ratio was
evaluated by 1H NMR on the crude product. Enantiomeric
excess was determined by HPLC analysis on chiral station-
ary phase. Absolute configurations were assigned on the
basis of the retention times,17and by comparison of the
[a]D sign9c with the data reported in the literature.
d 8.51 (d, J = 8.0 Hz, 1H), 7.88 (dd, J = 8.0, 2.0 Hz, 1H),
7.78 (d, J = 8.0 Hz, 1H), 7.58–7.48 (m, 3H), 7.45 (t,
J = 8.0 Hz, 1H), 4.37 (q, J = 6.5 Hz, 1H), 3.12 (dt,
J = 11.0, 3.0 Hz, 1H), 3.05 (m, 2H), 3.00 (m, 2H), 2.95
(m, 2H), 2.71 (dd, J = 11.0, 3.0 Hz, 1H), 2.55 (m, 2H),
2.23 (s, 3H), 1.53 (d, J = 6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 209.1 (1C), 139.7 (1C), 134.2 (1C),
131.5 (1C), 128.7 (1C), 127.8 (1C), 125.6–125.1 (4C),
124.6 (1C), 60.2 (1C), 60.0 (1C), 59.9 (1C), 57.4 (1C),
54.5 (1C), 46.8 (1C), 46.5 (1C), 45.0 (1C), 16.7 (1C);
20
½aꢀD ¼ ꢁ30:6ðc1; CHCl3Þ; HRMS m/z calcd 308.1889.
Found: 308.1893. Anal. Calcd for C20H24N2O: C, 77.89;
H, 7.84; N, 9.08; O, 5.19. Found: C, 77.92; H, 7.81; N, 9.11.
4.2.2. 3,7-Bis-((R)-10-phenyl-ethyl)-3,7-diaza-bicyclo[3.3.1]-
nonan-9-one 3. Compound 3 was prepared by slight mod-
ification of a previously reported procedure.14i To a
suspension of paraformaldehyde (225 mg, 7.5 mmol) in
30 mL of ethanol, (R)-1-(1-phenyl-ethyl)-piperidin-4-one15
(610 mg, 3 mmol), acetic acid (0.171 mL, 3 mmol), and
37% aq HCl (0.120 mL, 1.5 mmol) were added under a
nitrogen atmosphere. The mixture was heated at reflux
HPLC analysis conditions. trans-isomer: column, Chiral-
cel OD; eluant 95:5 n-hexane/i-PrOH; flow rate, 1 mL/
min; UV detector, 230 nm; retention time of (R,R)-isomer,
7.20 min (lit.17 5.15 min); retention time of (S,S)-isomer,
8.45 min (lit.17 5.90 min). Cis isomer: column, Chiralcel
OB; eluant 99:1 n-hexane/i-PrOH; flow rate, 1 mL/min;
UV detector, 230 nm; retention time of (S,R)-isomer,

G. Lesma et al. / Tetrahedron: Asymmetry 18 (2007) 659–663
663
27.40 min (lit.17 29.00 min); retention time of (R,S)-isomer,
Chem., Int. Ed. Engl. 1992, 31, 430–432; (c) Evans, D. A.;
Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem.
Soc. 1991, 113, 726–728; (d) Lowenthal, R. E.; Masamune, S.
Tetrahedron Lett. 1991, 32, 7373–7376.
25.80 min (lit.17 26.30 min).
4.4. Crystal data for 2
10. (a) Ito, K.; Katsuki, T. Tetrahedron Lett. 1993, 34, 2661–
2664; (b) Ito, K.; Katsuki, T. Synlett 1993, 638–640.
11. (a) Tanner, D.; Johansson, F.; Harden, A.; Andersson, P. G.
Tetrahedron 1998, 54, 15731–15738; (b) Kanemasa, S.;
Hamura, S.; Harada, E.; Yamamoto, H. Tetrahedron Lett.
1994, 35, 7985–7988.
M = 308.41, monoclinic, P21, a = 10.776(2), b = 12.421(2),
3
˚
˚
c = 12.452(2) A, b = 99.91(2)ꢁ, V = 1641.8(5) A , Z = 4,
T = 123 K, Dc = 1.248 g cmꢁ3, l(Mo-Ka) = 0.077 cmꢁ1
,
F(000) = 664; prism, 0.43 · 0.29 · 0.12 mm, Bruker
SMART diffractometer; 29,886 data collected, 5797
unique, Rint = 0.0455, 5047 with Io > 2r (I0). The structure
was solved by a direct method,18 and refined anisotro-
pically by matrix least-squares based on F2,19 to give
R1 = 0.0417, wR2 = 0.0988 for 5047 observed reflections
and 607 parameters and 151 restraints on C–H bond dis-
tances. The asymmetric unit contains two independent
molecules whose geometrical parameters are nearly equal.
The absolute configuration was chosen on the known
chirality the (R)-1-naphthalen-1-yl group, unchanged by
the chemical synthesis. Supplementary crystallographic
data were deposited as CCDC 635829 with the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.
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