Preparation of new chiral bisoxazoline ligands for the catalytic asymmetric intramolecular cyclopropanation of α-diazo-β-keto phenyl sulfone to afford a useful bicyclo[3.1.0]hexane derivative

Article abstract of DOI:10.1016/j.tetasy.2012.02.021

Herein we describe the preparation of novel chiral bisoxazoline ligands with various substituents at the bisoxazoline linkage, for use in the catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of α-diazo-β-keto phenyl-5-hexenyl sulfone to afford a simple, but useful, bicyclo[3.1.0]hexane derivative. The enantioselectivity of the CAIMCP of α-diazo-β-keto phenyl-5-hexenyl sulfone was improved and a product with 84% ee was obtained using 30 mol % of the catalyst, which was prepared in situ by CuOTf and the new bisoxazoline ligand with two 3,5-di-tert-butylbenzyl groups at the bisoxazoline linkage. The product was obtained in enantiomerically pure form by a single crystallization, enabling its use as a chiral building block.

Full text of DOI:10.1016/j.tetasy.2012.02.021

Tetrahedron: Asymmetry 23 (2012) 350–356
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Preparation of new chiral bisoxazoline ligands for the catalytic asymmetric
intramolecular cyclopropanation of a-diazo-b-keto phenyl sulfone to afford
a useful bicyclo[3.1.0]hexane derivative
⇑
Takashi Sawada, Masahisa Nakada
Department of Chemistry and Biochemistry, Advanced School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we describe the preparation of novel chiral bisoxazoline ligands with various substituents at the
bisoxazoline linkage, for use in the catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of
Received 21 January 2012
Accepted 20 February 2012
Available online 3 April 2012
a
-diazo-b-keto phenyl-5-hexenyl sulfone to afford a simple, but useful, bicyclo[3.1.0]hexane derivative.
The enantioselectivity of the CAIMCP of -diazo-b-keto phenyl-5-hexenyl sulfone was improved and a
a
product with 84% ee was obtained using 30 mol % of the catalyst, which was prepared in situ by CuOTf
and the new bisoxazoline ligand with two 3,5-di-tert-butylbenzyl groups at the bisoxazoline linkage.
The product was obtained in enantiomerically pure form by a single crystallization, enabling its use as
a chiral building block.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
R1
N
R1
N
: R1 = Me, R2 = Bn
1a
1b: R1 = Me, R2 = i-Pr
O
O
: R1 = Me, R2 = t-Bu
1c
Asymmetric catalysis with chiral metal complexes has attracted
considerable attention from synthetic organic chemists in recent
years because of its efficiency in producing chiral compounds.
Since chiral ligands play a pivotal role in the use of chiral metal
complexes, the development of various chiral ligands is an expand-
ing area of research. The C2-symmetric bisoxazoline ligands that
have two oxazoline rings separated by a single carbon atom with
two identical substituents can be easily prepared using the requi-
site chiral amino alcohols. Chiral amino alcohols can be readily de-
rived from commercially available chiral amino acids; hence, a
variety of bisoxazoline derivatives have been prepared and exten-
sively utilized in asymmetric catalysis in addition to other chiral
ligands.1
1d: R1 = Et, R2 = i-Pr
: R1 = Bn, R2 = i-Pr
1e
R2
N2
R2
R5
R5
R3
R4
SO2Mes
R3
CuOTf (10 mol %)
1e
n
SO2Mes
n
ligand
(15 mol %)
R4
O
93-98% ee
O
Mes = 2,4,6-trimethyl
4
5
(n = 1): (n = 2)
2
3
(n = 1): (n = 2)
n
CuOTf (10 mol %)
1b 1e
(15 mol %)
O
n
O
H
We have reported the catalytic asymmetric intramolecular
cyclopropanation (CAIMCP) of
N2
MesO2S
ligand
or
a-diazo-b-keto aryl sulfones, which
MesO2S
1e
n = 1, : 96% ee
H
proceeds in a high yield and with excellent enantioselectivity
1b
n = 2, : 97% ee
(Scheme 1).2 The CAIMCP of
a-diazo-b-keto aryl sulfones has been
6
7
8
9
(n = 1): (n = 2)
(n = 1): (n = 2)
utilized for natural product synthesis,3 and has promoted related
studies, proving the potential utility and wide applicability of the
CAIMCP approach.4 During these studies, it was found that the
bisoxazoline ligand with two benzyl groups at the linkage was
effective in improving the enantioselectivity of the CAIMCP of
Scheme 1. Catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of
-diazo-b-keto aryl sulfones.
a
CuOTf and ligand 1e.2a The cyclopropanation occurs preferentially
at the Re-face (defined by the Cu@CꢀC arrangement) of the
carbene complex, since steric hindrance would be encountered
at the Si-face. Thus, when the double bond approaches from the
Si-face, the carbene C atom would become pyramidal in the transi-
tion state and the mesityl sulfonyl group would interact unfavor-
ably with both the isopropyl group and the benzyl group of the
ligand. Conversely, reaction at the Re-face would be preferred
a
-diazo-b-keto aryl sulfones.2,3
Figure 1 shows the proposed transition state models to explain
the enantioselectivity of the CAMICP of 2 (R3 = R4 = R5 = H) with
⇑
Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.02.021

T. Sawada, M. Nakada / Tetrahedron: Asymmetry 23 (2012) 350–356
351
1) NaCN, DMSO
80 °C, 5h, 95%
SO2Np
2) 1-bromo-2-pentyne
NaI, K2CO3, DMF, rt, 5h
O
Np = 1-naphthyl
13
CN
CN
R
+
SO2Np
SO2Np
O
OR
Figure 1. Proposed models A and B for the CAIMCP of 2 (R3 = R4 = R5 = H) with
ligand 1e and CuOTf.
(R = 2-pentynyl)
(R = 2-pentynyl)
14o
14c
yield 36%
yield 59%
Scheme 3. Reaction of 13 with sodium cyanide and subsequent alkylation with 1-
bromo-2-pentyne.
because the unfavorable interactions with the mesityl sulfonyl
group would be negligible in the transition states arising from
model A or model B.
Table 1
The enantioselectivity of the CAIMCP of 2 (R3 = R4 = R5 = H) with
CuOTf and ligand 1e is well explained by model A, because the
transition state via model B would be energetically unfavorable
due to steric repulsion between the terminal alkene and the car-
bene complex.
CAIMCPs of a-diazo-b-keto sulfone 15 with bisoxazoline ligands 1a–e
R1
R1
: R1 = Me, R2 = Bn
1b: R1 = Me, R2 = i-Pr
1c
1a
O
O
: R1 = Me, R2 = t-Bu
1d: R1 = Et, R2 = i-Pr
1e
N
N
: R1 = Bn, R2 = i-Pr
In these models, the mesityl sulfonyl group and the benzyl
group of the ligand have crucial roles in the enantioselective dis-
crimination. Thus, the high enantioselectivities observed in the
CAIMCP using the mesityl sulfones and ligand 1e are suitably ex-
plained by the increase in unfavorable interactions.
As described above, the use of a bulky mesityl sulfone improves
the enantioselectivity of the CAIMCP.2 However, it makes the
transformation of products difficult due to the bulky mesityl sul-
fone.3c For example, the attempted C-allylation and propargylation
of compound 11 (Scheme 2), which was derived from the ring-
opening reaction of 10 with sodium cyanide, afforded O-alkylated
products 12o as the major products.3c
R2
R2
H
N2
CuOTf (10 mol %)
ligand (15 mol %)
SO2Ph
SO2Ph
16
toluene, temp, time
O
O
15
Entry
Ligand
Temp
Time (h)
Yield (%)
eea (%)
1
2
3
4
5
1a
1b
1c
1d
1e
rt
rt
2
2
5.5
5.5
2
67
91
61
67
61
75
65
32
72
73
50 °C
rt
rt
a
Ee determined by HPLC. For HPLC conditions, see Section 4.
CN
RBr, NaI
NaCN, DMSO
K2CO3
80oC, 5h, 93%
SO2Mes
SO2Mes
rt, 5h, DMF
O
O
with ligand 1a, which affords cyclopropane 16 with 75% ee. Com-
pound 16 is one of the simplest bicyclo[3.1.0]hexane derivatives
and various transformations are possible, making enantiomerically
pure 16 an extremely useful chiral building block. Compound 16 is
highly crystalline and can be made in enantiomerically pure form
by recrystallization when the ee is high. However, repeated recrys-
tallization was needed to obtain enantiopure 16 because of its rel-
atively low ee. Therefore, we started to investigate a new chiral
10
11
CN
CN
R
+
SO2Mes
SO2Mes
OR
O
12o
12o
(R = allyl)
(R = propargyl)
12c
12c
yield 91%
yield 66%
(R = allyl)
yield 6%
bisoxazoline ligand that would be effective for the CAIMCP of
diazo-b-keto phenyl sulfone 15.
a-
(R = propargyl) yield 27%
Scheme 2. Reaction of 10 with sodium cyanide and subsequent alkylation with 1-
bromo-2-pentyne.
2. Results and discussion
As shown in Scheme 3, however, this problem has been over-
come by changing mesityl sulfone 10 to 1-naphthyl sulfone 13,
which generates the C-alkylated product 14c as the major prod-
As noted above, the enantioselectivity of the CAIMCP varies
with the substituent at the bisoxazoline linkage. Hence, we pre-
pared bisoxazoline ligands with a variety of substituents at the bis-
oxazoline linkage in order to improve the enantioselectivity of the
CAIMCP of 15.
Several methods have been reported for the preparation of bis-
oxazoline ligands,1d–f and two short and effective methods have
been reported as shown in Scheme 4. One is the alkylation of bis-
oxazoline ligands possessing no substituents at the bisoxazoline
linkage (method 1).5 The other is bisoxazoline formation by the
reaction of 2 equiv of amino alcohol with a disubstituted malono-
nitrile in the presence of an acid (method 2).6
uct.3c Nonetheless, the preparation of
a
-diazo-b-keto 1-naphthyl
sulfone requires the use of 1-naphthyl sulfone, which is widely
unavailable. The use of -diazo-b-keto phenyl sulfone is more
a
practical because it can be readily prepared using the commercially
available methyl phenyl sulfone. Therefore, an improvement in the
enantioselectivity of the CAIMCP of
is highly desirable.
a-diazo-b-keto phenyl sulfone
Table 1 summarizes the CAIMCP of
a-diazo-b-keto phenyl sul-
fone 15.2a The best enantioselectivity was observed for the CAIMCP

352
T. Sawada, M. Nakada / Tetrahedron: Asymmetry 23 (2012) 350–356
R1
N
R1
N
Another research group has also reported on the preparation of
ligand 1q by method 1.7 However, the yield of the alkylation step
was 55%, which was lower than the overall yield (66%, two steps)
of 1q by method 2 (Table 2). This result could indicate that method
2 is more effective than method 1 for the preparation of bisoxazo-
line ligands with bulky substituents at the bisoxazoline linkage.
Table 3 shows the results of the CAIMCPs of 15 with 1f–q. All
the CAIMCPs of 15 were completed within three hours and the
absolute configurations of all of the products were the same as
those shown in Table 1. The ee obtained from the use of the ligand
with ethyl groups 1d (72% ee, Table 1) was almost the same as
those obtained using the ligands with i-butyl 1f (70% ee), c-hex-
ylmethyl 1g (72% ee), and cyclohexanediyl 1i (71% ee) groups.
The ee obtained from the use of the ligand with a c-hexylmethyl
group 1g (72% ee) is the same as that obtained when using the li-
gand with a benzyl group 1e (72% ee). This result could indicate
that the effect of the benzyl group on the enantioselectivity of
the CAIMCP could be attributed to the steric bulkiness. However,
method 1
O
O
O
O
1) base (2 equiv)
2) R1X (2 equiv)
N
N
R2
R2
R2
R2
R1
N
R1
N
method 2
amino alcohol
(2 equiv)
O
O
R1
NC
R1
CN
ZnCl2
R2
R2
Scheme 4. Alkylation of bisoxazoline ligands with no substituents at the bisoxaz-
oline linkage (method 1) and bisoxazoline formation by the reaction of an amino
alcohol with a substituted malononitrile (method 2).
Both of these methods for synthesizing bisoxazoline ligands re-
quire only three steps from commercially available materials.
However, as described later, when the alkylation reagent is bulky,
method 1 was found to be relatively low-yielding.7 On the other
hand, we found that the desired bisoxazolines could be efficiently
prepared by method 2, even when the substituent of the malono-
nitrile was bulky. The efficiency of method 2 could be attributed
to the fact that the chelate formed by the generated bisoxazoline
with zinc chloride would be a driving force to in increasing the
yield. In addition, our preliminary experiments indicated that the
reaction of malononitrile with relatively bulky alkylating reagents
afforded the corresponding product in a good to excellent yield.
Hence, method 2 was employed to prepare bisoxazolines.
In order to compare the data obtained by the CAIMCP of 15
using ligands 1b, 1d, and 1e with those that would be obtained
using new chiral ligands, L-valinol was used for step B in the prep-
aration of new bisoxazoline ligands. Thus, bisoxazoline ligands
with isobutyl 1f, cyclohexyl 1g, phenethyl 1h, cyclohexanediyl 1i,
substituted benzyls 1j–p, and 2-naphthylmethyl 1q groups at the
bisoxazoline linkage were prepared (Table 2).
The alkylation of malononitrile (step A) proceeded smoothly
when using either alkylbromide or alkyliodide with DBU to afford
the di-alkylated products 17f–q in good yield (from 67% to quanti-
tative yield).8 The yield of the subsequent bisoxazoline formation
depended on the type of substituent on the malononitrile
derivatives. Thus, the yield of step B was 96% in the case of the
2-naphthylmethyl group, and 19% and 17% in the cases of cyclo-
hexylmethyl and 3,5-di-tert-butylbenzyl groups, respectively. The
low yields were attributed to the steric hindrance derived from
the bulky substituents at the bisoxazoline linkage.
the benzene ring is capable of p–p interactions with the aryl sulfo-
nyl group of the substrate and so this could also play a part.
Since a phenethyl group is more bulky than an ethyl group, the
ee of the product obtained by use of the ligand with a phenethyl
group 1h was expected to be higher than that observed in the reac-
tion with the ligand with an ethyl group 1d (72% ee, Table 1). How-
ever, this was found to not be the case and the ee was slightly
lower with the use of 1h (67% ee).
The ee values observed in reactions with the use of ligands with
m-tolyl 1k (72% ee), p-tolyl 1l (72% ee), p-phenylbenzyl 1m (72%
ee), and p-tert-butylbenzyl 1m (74% ee) are almost the same as
those observed in the reaction using the ligand with a benzyl group
1e (73% ee, Table 1). However, the ee slightly increased with the
use of the ligand with 3,5-dimethylbenzyl group 1o (76% ee), and
the ee increased significantly to 81% ee in the case of the
ligand with the 3,5-di-tert-butylbenzyl group 1p. Interestingly,
the ee decreased with the use of the ligand with an o-tolyl group
1j (63% ee), indicating that the ee could be altered not only by
the bulkiness, but also by the position of the substituents on the
benzene ring.
Considering the bulkiness and the position of the substituent on
the naphthyl group, the ee achieved using the ligand with a 2-
naphthyl group 1q should at least be the same as those obtained
by the ligands with an m-tolyl 1k (72% ee) or p-tolyl 1l (72% ee)
groups. However, it was found that the ee was lower (67% ee) than
that obtained using the ligand with a benzyl group 1e (73% ee,
Table 1). The reason for the low ee cannot therefore be solely
Table 2
Preparation of bisoxazoline ligands 1f–q by method 2
R
R
R
R
RX (2.2. equiv)
L-valinol (3.0 equiv)
O
O
NC
CN
DBU (2.2 equiv)
DMF, 80 °C, 1h
NC
17f-q
CN
ZnCl2 (3.0 equiv)
PhCl, reflux, 1d
N
N
i-Pr
i-Pr
1f-q
A
B
1f
1g
1h
1i
1j
1k
1l
1m
Ph
1n
t-Bu
1o
1p
1q
t-Bu
t-Bu
R
X
2
I
Br
80
19
Br
67
75
Br
95
85
Br
97
25
Br
94
86
Br
Quant.
47
Br
94
22
I
83
40
Br
90
58
Br
99
17
Br
69
96
Step A yielda (%) 88
Step B yielda (%) 37
a
Isolated yield.

T. Sawada, M. Nakada / Tetrahedron: Asymmetry 23 (2012) 350–356
353
Table 3
The CAIMCP of 15 with bisoxazoline ligands 1f–q
H
N2
CuOTf (10 mol %)
ligand (15 mol %)
SO2Ph
SO2Ph
toluene, rt
O
O
16
1n
t-Bu
15
1f
1g
1h
1i
1j
1k
1l
1m
Ph
1o
1p
1q
t-Bu
t-Bu
R
2
Time (h)
Yielda (%)
eeb (%)
4
90
70
2
93
72
1
87
67
1
79
71
2
77
63
2
72
72
3
63
72
1
80
72
2
80
74
3
74
76
2
70
81
3
76
67
a
Isolated yield.
b
Ee determined by HPLC. For HPLC conditions, see Section 4.
attributed to the bulkiness of the substituent. As previously men-
tioned, the ee value obtained using the ligand with a bulky phen-
ethyl group 1h was lower than that obtained using the ligand
with an ethyl group 1d. Combining these observations suggests
that the aromatic ring may have a specific effect on the ee, inde-
pendent of any effects due to the bulkiness of the substituents.
Since the CAIMCP of 15 with ligand 1p afforded 16 with 81% ee,
the reaction conditions were further optimized. We observed that
carrying out the CAIMCP at low temperature could improve the
enantioselectivity.4e Hence, the reaction of 15 was carried out at
0 °C (Scheme 5). As a result, although the reaction proceeded
slowly at 0 °C even when 30 mol % of the catalyst was used, 16
was obtained in 64% yield and 84% ee. The highly crystalline nature
herein as well as their preparation method could be useful for
research in the field of asymmetric catalysis.
4. Experimental
4.1. General procedures
1H and 13C NMR spectra were recorded on JEOL AL-270, AL-300,
and Lambda 500 spectrometers. 1H and 13C chemical shifts are re-
ported in ppm downfield from tetramethylsilane (TMS, d scale)
with the solvent resonances as internal standards. The following
abbreviations were used to explain the multiplicities: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; band, several over-
lapping signals; br, broad. IR spectra were recorded on a JASCO
FT/IR-8300. Optical rotations were measured using a 2 mL cell with
a 1 dm path length on a JASCO DIP-1000. Chiral HPLC analysis was
performed on a JASCO PU-980 and UV-970. Mass spectra and ele-
mental analyses were provided at the Materials Characterization
Central Laboratory, Waseda University. All reactions were carried
out under an argon atmosphere with dry, freshly distilled solvents
under anhydrous conditions, unless otherwise noted. All reactions
were monitored by thin-layer chromatography carried out on
0.25 mm E. Merck silica gel plates (60F-254) using UV light as a
visualizing agent and phosphomolybdic acid and heat as develop-
ing agents. E. Merck silica gel (60, particle size 0.040–0.063 mm)
was used for flash chromatography. Preparative thin-layer chroma-
tography (PTLC) separations were carried out on self-made 0.3 mm
E. Merck silica gel plates (60F-254). THF and Et2O were distilled
from sodium/benzophenone ketyl. Toluene was distilled from so-
dium. MeOH was distilled with a small amount of magnesium
and I2. Benzene, MeCN were distilled from CaH2, and all other re-
agents were purchased from Aldrich, TCI, or Kanto Chemical Co.
Ltd. 1-Siazo-1-phenylsulfonyl-5-hexene-2-one 15 was prepared
according to the procedure reported in the literature.2a
H
N2
CuOTf (30 mol %)
1p
ligand
(50 mol %)
SO2Ph
SO2Ph
16
toluene, 0 °C, 30h
64%, 84% ee
O
O
15
Scheme 5. The CAIMCP of 15 with bisoxazoline ligand 1p at 0 °C.
of 16 allowed us to obtain an enantiomerically pure compound by
a single recrystallization.
3. Conclusion
In conclusion, various novel bisoxazoline ligands possessing
bulky substituents at the bisoxazoline linkage have been success-
fully prepared. We have demonstrated that the bisoxazoline li-
gands with bulky substituents, including a 3,5-di-tert-butylbenzyl
group, at the bisoxazoline linkage could be efficiently prepared
by the alkylation of malononitrile and subsequent bisoxazoline for-
mation by the reaction of an amino alcohol in the presence of zinc
chloride. The ligands prepared were evaluated for the CAIMCP of
4.2. Preparation of dialkylated malononitriles 17f–q
a-diazo-b-keto-5-hexenyl phenyl sulfone 15, and a product with
84% ee was obtained using 30 mol % of the catalyst, which was pre-
pared in situ by CuOTf and the new bisoxazoline ligand with two
3,5-di-tert-butylbenzyl groups at the bisoxazoline linkage. An
enantiomeric excess value of 84% is the highest ee to have been
reported so far for the CAIMCP of 15; the product was made
enantiomerically pure by a single crystallization, enabling its use
as a chiral building block. The bisoxazoline ligands developed
Dialkylated malononitriles 17f–q were prepared by the alkyl-
ation of malononitrile according to the reported procedure.8
17h,8a 17i,8b and 17l8a are known compounds.
Procedure A: To a solution of malononitrile in DMF (30 mL per
gram of malononitrile) were added DBU (2.2 equiv) and alkyl ha-
lide (2.2 equiv), and the reaction mixture was stirred at 80 °C for
2 h. After the reaction was completed, the reaction mixture was

354
T. Sawada, M. Nakada / Tetrahedron: Asymmetry 23 (2012) 350–356
cooled to room temperature and water (150 mL per gram of mal-
ononitrile) and dichloromethane (150 mL per gram of malononitri-
le) was added to the reaction mixture. The aqueous layer was
extracted with dichloromethane (150 mL per gram of malononitri-
le) and the combined organic layer was washed with brine, dried
over MgSO4, and evaporated. The residue was purified by silica
gel chromatography to afford the dialkylated malononitrile.
4.2.6. 2,2-Di(4-tert-Butylphenylmethyl)malononitrile 17n
This compound was prepared by Procedure A as described using
p-tert-butylbenzyliodide. A white solid (89%) was obtained after
purification by silica gel chromatography (chloroform/metha-
nol = 50:1): Rf = 0.35 (hexane/ethyl acetate = 10:1); mp 178–
180 °C; 1H NMR (300 MHz, CDCl3) d = 7.44–7.38 (m, 4H), 7.35–
7.30 (m, 4H), 3.21 (s, 4H), 1.33 (s, 18H); 13C NMR (125 MHz, CDCl3)
d = 151.8, 130.1, 129.1, 126.0, 115.2, 43.1, 41.4, 34.7, 31.4; IR (neat)
mmax 2959, 2902, 1518, 1505, 1469, 1449, 1360, 1268, 1125, 1106,
1019, 837, 825, 677, 666, 554 cmꢀ1; HRMS (FAB) [M+H]+ calculated
for C25H31N2: 359.2409, found: 359.2399.
4.2.1. 2,2-Bis(isobutyl)malononitrile 17f
This compound was prepared by Procedure A as described using
isobutyl bromide. A colorless liquid (88%) was obtained after puri-
fication by silica gel chromatography (hexane/ethyl ace-
tate = 10:1): Rf = 0.53 (hexane/ethyl acetate = 4:1); 1H NMR
(300 MHz, CDCl3) d = 2.10 (tq, J = 7.0, 6.9 Hz, 2H), 1.83 (d,
J = 6.6 Hz, 4H), 1.12 (d, J = 7.0 Hz, 12H); 13C NMR (75 MHz, CDCl3)
d = 116.2, 47.1, 34.6, 26.3, 22.9; IR (neat) mmax 3061, 2937, 2903,
1469, 1389, 1371, 1173, 1025, 923 cmꢀ1; HRMS (FAB) [M+H]+ cal-
culated for C18H19N2: 179.1548, found: 179.1548.
4.2.7. 2,2-Bis(3,5-dimethylphenylmethyl)malononitrile 17o
This compound was prepared by Procedure A as described using
3,5-dimethylbenzylbromide. A white solid (90%) was obtained
after purification by silica gel chromatography (hexane/ethyl
acetate = 10:1): Rf = 0.73 (hexane/ethyl acetate = 4:1); mp 163–
165 °C; 1H NMR (300 MHz, CDCl3) d = 7.04–6.96 (m, 6H), 3.14 (s,
4H), 2.33 (s, 12H); 13C NMR (125 MHz, CDCl3) d = 138.6, 132.0,
130.5, 128.2, 115.2, 43.4, 41.0, 21.4; IR (neat) mmax 2930, 1608,
1468, 1448, 1380, 1308, 1040, 854, 733, 715, 675, 660 cmꢀ1; HRMS
(FAB) [M+H]+ calculated for C21H23N2: 303.1861, found: 303.1861.
4.2.2. 2,2-Bis(cyclohexylmethyl)malononitrile 17g
This compound was prepared by Procedure A as described using
cyclohexylmethylbromide. A white solid (80%) was obtained after
purification by silica gel chromatography (hexane/ethyl
acetate = 20:1): Rf = 0.76 (hexane/ethyl acetate = 4:1); mp
90–92 °C; 1H NMR (270 MHz, CDCl3) d = 1.98–1.88 (m, 4H), 1.83–
1.63 (m, 12H), 1.42–0.98 (m, 10H); 13C NMR (125 MHz, CDCl3)
d = 116.5, 46.1, 35.6, 34.2, 33.5, 25.9; IR (neat) mmax 2920, 2849,
4.2.8. 2,2-Bis(3,5-di-tert-butylphenylmethyl)malononitrile 17p
This compound was prepared by Procedure A as described using
3,5-di-tert-butylbenzylbromide. A white solid (99%) was obtained
after purification by silica gel chromatography (chloroform/
methanol = 50:1): Rf = 0.48 (hexane/ethyl acetate = 10:0); mp
200–202 °C; 1H NMR (270 MHz, CDCl3) d = 7.44–7.42 (m, 2H),
7.24–7.22 (m, 4H), 3.24 (s, 4H), 1.34 (s, 36H); 13C NMR
(125 MHz, CDCl3) d = 151.5, 131.4, 124.8, 122.5, 115.3, 44.3, 41.9,
35.0, 31.5; IR (neat) mmax 2964, 2954, 2903, 2867, 1600, 1476,
1447, 1379, 1347, 1262, 1006, 971, 895, 843, 700, 572, 470 cmꢀ1
;
HRMS (FAB) [M+H]+ calculated for C17H27N2: 259.2174, found:
259.2210.
4.2.3. 2,2-Di(2-methylphenylmethyl)malononitrile 17j
This compound was prepared by Procedure A as described using
o-methylbenzylbromide. A white solid (97%) was obtained after
purification by silica gel chromatography (hexane/ethyl ace-
tate = 10:1): Rf = 0.55 (hexane/ethyl acetate = 4:1); mp 92–95 °C;
1H NMR (270 MHz, CDCl3) d = 7.49–7.41 (m, 2H), 7.34–7.20 (m,
6H), 3.37 (s, 4H), 2.40 (s, 6H). 13C NMR (125 MHz, CDCl3)
d = 137.5, 31.3, 130.9, 130.7, 128.9, 126.6, 115.5, 40.2, 39.8, 20.0;
IR (neat) mmax 1494, 1448, 1384, 1126, 1032, 772, 754, 734, 425,
667, 448 cmꢀ1; HRMS (FAB) [M+H]+ calculated for C19H19N2:
275.1548, found: 275.1502.
1463, 1447, 1363, 1248, 1202, 879, 732, 718, 706 cmꢀ1
;
HRMS (FAB) [M+H]+ calculated for C33H47N2: 471.3739, found:
471.3739.
4.2.9. 2,2-Bis(2-naphthyl)malononitrile 17q
This compound was prepared by Procedure A as described using
2-(bromomethyl)naphthalene. A white solid (69%) was obtained
after purification by silica gel chromatography (chloroform/
methanol = 10:1): Rf = 0.29 (hexane/ethyl acetate = 4:1); mp
195–197 °C; 1H NMR (300 MHz, CDCl3) d = 7.92–7.81 (m, 8H),
7.57–7.45 (m, 6H), 3.44 (s, 4H); 13C NMR (75 MHz, CDCl3)
d = 133.3, 133.2, 129.8, 129.4, 128.8, 128.0, 127.7, 127.5, 126.7,
126.6, 115.0, 43.6, 41.1; IR (neat) mmax 3056, 2926, 1600, 1509,
1371, 1127, 967, 867, 827, 779, 756, 687, 484 cmꢀ1; HRMS (FAB)
[M+H]+ calculated for C25H19N2: 347.1548, found: 347.1576.
4.2.4. 2,2-Di(3-methylphenylmethyl)malononitrile 17k
This compound was prepared by Procedure A as described
above using m-methylbenzylbromide. A white solid (94%) was ob-
tained after purification by silica gel chromatography (hexane/
ethyl acetate = 10:1): Rf = 0.58 (hexane/ethyl acetate = 4:1); mp
124–126 °C; 1H NMR (270 MHz, CDCl3) d = 7.33–7.26 (m, 2H),
7.22–7.17 (m, 6H), 3.20 (s, 4H), 2.38 (s, 6H). 13C NMR (125 MHz,
CDCl3) d = 138.8, 132.0, 131.1, 129.7, 128.9, 127.4, 115.1, 43.4,
41.1, 21.5; IR (neat) mmax 1486, 144, 1266, 1099, 791, 751, 731,
708, 436 cmꢀ1; HRMS (FAB) [M+H]+ calculated for C19H19N2:
275.1548, found: 275.1472.
4.3. Preparation of bisoxazoline ligands 1f–q
Bisoxazoline ligands 1f–q were prepared from the correspond-
ing dialkylated malononitriles 17f–q according to the procedure
reported in the literature.2a Compounds 1f9 and 1q8 are known
compounds.
Procedure B: To a solution of dialkylated malononitrile in o-
dichlorobenzene (30 mL per gram of dialkylated malononitrile)
4.2.5. 2,2-Di(4-phenylphenylmethyl)malononitrile 17m
This compound was prepared by Procedure A as described using
p-phenylbenzylbromide. A white solid (94%) was obtained after
purification by silica gel chromatography (chloroform/
methanol = 50:1): Rf = 0.40 (hexane/ethyl acetate = 4:1); mp
245–248 °C; 1H NMR (270 MHz, CDCl3) d = 7.67–7.59 (m, 8H),
7.55–7.33 (m, 10H), 3.33 (s, 4H); 13C NMR (125 MHz, CDCl3)
d = 141.9, 140.3, 130.9, 130.8, 129.0, 127.8, 127.7, 127.2, 115.1,
43.2, 41.3; IR (neat) mmax 1485, 1446, 1007, 831, 767, 738, 725,
696, 671, 548, 499, 408 cmꢀ1; HRMS (FAB) [M+H]+ calculated for
were added zinc chloride (3.0 equiv) and L-valinol (3.0 equiv),
and the reaction mixture was stirred at 150 °C for 12 h. After the
reaction was complete, the reaction mixture was cooled to room
temperature. To the reaction mixture were added water (3 mL
per gram of dialkylated malononitrile) and ethylenediamine
(6 mL per gram of dialkylated malononitrile), and the reaction mix-
ture was stirred at room temperature for 1 h. Water (30 mL per
gram of dialkylated malononitrile) and dichloromethane (30 mL
per gram of dialkylated malononitrile) was added to the reaction
mixture and the aqueous layer was extracted with dichlorometh-
C29H23N2: 399.1861, found: 399.1793.

T. Sawada, M. Nakada / Tetrahedron: Asymmetry 23 (2012) 350–356
355
ane (30 mL per gram of dialkylated malononitrile). The combined
4.3.5. (S)-4,5-Dihydro-2-(2-((S)-4,5-dihydro-4-isopropyloxazol-
organic layer was washed with brine, dried over MgSO4, and evap-
orated. The residue was purified by silica gel chromatography to
afford the bisoxazoline ligand.
2-yl)-1,3-di-m-tolylpropan-2-yl)-4-isopropyloxazole 1k
This compound was prepared from 17k by Procedure B as de-
scribed. A white solid (86%) was obtained after purification by sil-
ica gel chromatography (hexane/ethyl acetate = 10:1): Rf = 0.65
(hexane/ethyl acetate = 2:1); mp 62–64 °C; 1H NMR (300 MHz,
CDCl3) d = 7.17–7.10 (m, 2H), 7.08–6.99 (m, 6H), 4.21–4.10 (m,
2H), 3.95–3.80 (m, 4H), 3.36 (d, J = 13.9 Hz, 2H), 3.18 (d,
J = 13.9 Hz, 2H), 2.30 (s, 6H), 1.74–1.62 (m, 2H), 0.90 (d,
J = 6.6 Hz, 6H), 0.82 (d, J = 6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d = 166.3, 137.1, 136.9, 131.4, 127.7, 127.5, 127.2, 72.0, 69.7, 48.2,
39.2, 32.5, 21.4, 18.9, 17.9; IR (neat) mmax 2963, 2931, 2905, 1662,
4.3.1. (S)-2-(1,3-Dicyclohexyl-2-((S)-4,5-dihydro-4-isopropyl-
oxazol-2-yl)propan-2-yl)-4,5-dihydro-4-isopropyloxazole 1g
This compound was prepared from 17g by Procedure B as de-
scribed. A white solid (19%) was obtained after purification by sil-
ica gel chromatography (hexane/ethyl acetate = 10:1): Rf = 0.68
(hexane/ethyl acetate = 2:1); mp 68–70 °C; 1H NMR (270 MHz,
CDCl3) d = 4.19–4.09 (m, 2H), 3.96–3.85 (m, 4H), 2.05–1.74 (m,
6H), 1.71–1.52 (m, 10H), 1.42–0.88 (m, 12H), 0.94 (d, J = 6.9 Hz,
6H), 0.86 (d, J = 6.9 Hz, 6H); 13C NMR (125 MHz, CDCl3) d = 168.2,
71.9, 69.3, 45.0, 39.9, 35.1, 34.0, 33.6, 32.4, 26.6, 26.6, 26.4, 19.0,
17.7; IR (neat) mmax 2954, 2923, 2850, 154, 1470, 1447, 1207,
1169, 1022, 1001, 973, 953, 926 cmꢀ1; HRMS (FAB) [M+H]+ calcu-
1465, 1363, 1185, 1175, 1015, 963, 954, 893, 775, 699, 585 cmꢀ1
;
HRMS (FAB) [M+H]+ calculated for C29H39N2O2: 447.3012, found:
447.3012; ½a 2D0
¼ ꢀ100 (c 0.53, MeOH).
ꢁ
4.3.6. (S)-4,5-Dihydro-2-(2-((S)-4,5-dihydro-4-isopropyloxazol-
2-yl)-1,3-di-p-tolylpropan-2-yl)-4-isopropyloxazole 1l
lated for C27H47N2O2: 431.3638, found: 431.3600; ½a D20
¼ ꢀ88:0
ꢁ
(c 0.55, MeOH).
This compound was prepared from 17l by Procedure B as de-
scribed. A white solid (47%) was obtained after purification by sil-
ica gel chromatography (hexane/ethyl acetate = 10:1): Rf = 0.50
(hexane/ethyl acetate = 4:1); mp 55–58 °C; 1H NMR (270 MHz,
CDCl3) d = 7.16–7.09 (m, 4H), 7.08–7.01 (m, 4H), 4.23–4.08 (m,
2H), 3.96–3.78 (m, 4H), 3.35 (d, J = 13.9 Hz, 2H), 3.16 (d,
J = 13.9 Hz, 2H), 2.30 (s, 6H), 1.78–1.60 (m, 2H), 0.90 (d,
J = 6.9 Hz, 6H), 0.82 (d, J = 6.9 Hz, 6H); 13C NMR (125 MHz, CDCl3);
d = 166.4, 136.0, 134.0, 130.4, 128.7, 72.1, 69.8, 48.4, 38.8, 32.6,
21.1, 19.1, 18.0; IR (neat) mmax 2958, 2904, 1657, 1515, 1239,
1189, 1173, 1114, 1032, 1014, 986, 962, 952, 857, 809, 711, 563,
543, 486 cmꢀ1; HRMS (FAB) [M+H]+ calculated for C29H39N2O2:
4.3.2. (S)-4,5-Dihydro-2-(3-((S)-4,5-dihydro-4-isopropyloxazol-2-yl)-
1,5-diphenylpentan-3-yl)-4-isopropyloxazole 1h
This compound was prepared from 17h by Procedure B as de-
scribed. A white solid (75%) was obtained after purification by sil-
ica gel chromatography (hexane/ethyl acetate = 4:1): Rf = 0.49
(hexane/ethyl acetate = 2:1); mp 40–42 °C; 1H NMR (300 MHz,
CDCl3) d = 7.32–7.14 (m, 10H), 4.26–4.13 (m, 2H), 4.03–3.92 (m,
4H), 2.67–2.56 (m, 4H), 2.47–2.24 (m, 4H), 1.87–1.72 (m, 2H),
0.96 (d, J = 6.6 Hz, 6H), 0.89 (d, J = 7.0 Hz, 6H); 13C NMR
(125 MHz, CDCl3) d = 166.8, 142.1, 128.6, 128.4, 125.9, 72.0, 69.9,
46.2, 35.3, 32.6, 30.8, 18.9, 18.0; IR (neat) mmax 2954, 1647, 1217,
1189, 1052, 1030, 971, 936, 754, 698, 502, 478 cmꢀ1; HRMS
(FAB) [M+H]+ calculated for C29H39N2O2: 447.3012, found:
447.3012, found: 447.3017; ½a D20
¼ ꢀ92:9 (c 0.64, MeOH).
ꢁ
4.3.7. (S)-2-(1,3-Bis(4-phenylphenyl)-2-((S)-4,5-dihydro-4-iso-
propyloxazol-2-yl)propan-2-yl)-4,5-dihydro-4-isopropyloxazole
1m
447.3010; ½a 2D0
¼ ꢀ64:4 (c 0.55, MeOH).
ꢁ
This compound was prepared from 17m by Procedure B as de-
scribed. A white solid (22%) was obtained after purification by silica
gel chromatography (hexane/ethyl acetate = 10:1): Rf = 0.26 (hex-
ane/ethyl acetate = 4:1); mp 53–57 °C; 1H NMR (270 MHz, CDCl3);
d = 7.61–7.55 (m, 4H), 7.54–7.39 (m, 8H), 7.37–7.30 (m, 6H),
4.25–4.17 (m, 2H), 3.99–3.85 (m, 4H), 3.48 (d, J = 14.2 Hz, 2H),
3.31 (d, J = 14.2 Hz, 2H), 1.78–1.65 (m, 2H), 0.90 (d, J = 6.6 Hz, 6H),
0.83 (d, J = 6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3); d = 166.3,
141.2, 139.6, 136.2, 131.0, 128.8, 127.2, 127.1, 126.8, 72.1, 70.0,
48.4, 39.1, 32.6, 19.0, 18.0; IR (neat) mmax 2955, 2930, 2895, 2870,
1656, 1486, 1466, 1171, 1022, 1007, 958, 855, 825, 758, 728, 695,
560,520 cmꢀ1; HRMS (FAB) [M+H]+ calculated for C39H43N2O2:
4.3.3. (S)-4,5-Dihydro-2-(1-((S)-4,5-dihydro-4-isopropyloxazol-
2-yl)cyclohexyl)-4-isopropyloxazole 1i
This compound was prepared from 17i by Procedure B as de-
scribed. A colorless oil (85%) was obtained after purification by sil-
ica gel chromatography (hexane/ethyl acetate = 2:1): Rf = 0.35
(hexane/ethyl acetate = 2:1); 1H NMR (300 MHz, CDCl3) d = 4.22–
4.13 (m, 2H), 4.03–3.93 (m, 4H), 2.17–1.92 (m, 4H), 1.89–1.73
(m, 2H), 1.39–1.72 (m, 6H), 0.93 (d, J = 7.0 Hz, 6H), 0.87 (d,
J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) d = 167.3, 43.2, 32.7,
32.4, 25.5, 22.7, 18.8, 17.9; IR (neat) mmax 2954, 2932, 2870, 1655,
1466, 1450, 1344, 1226, 1208, 1124, 1046, 1031, 980, 942,
904 cmꢀ1
;
HRMS (FAB) [M+H]+ calculated for C18H31N2O2:
571.3325, found: 571.3373; ½a D20
¼ ꢀ20:7 (c 0.41, MeOH).
ꢁ
307.2386, found: 307.2386; ½a D23
¼ ꢀ84:2 (c 0.70, MeOH).
ꢁ
4.3.8. (S)-2-(1,3-Bis(4-tert-butylphenyl)-2-((S)-4,5-dihydro-4-iso-
propyloxazol-2-yl)propan-2-yl)-4,5-dihydro-4-isopropyloxazole
1n
4.3.4. (S)-4,5-Dihydro-2-(2-((S)-4,5-dihydro-4-isopropyloxazol-
2-yl)-1,3-di-o-tolylpropan-2-yl)-4-isopropyloxazole 1j
This compound was prepared from 17j by Procedure B as de-
scribed. A white solid (25%) was obtained after purification by sil-
ica gel chromatography (hexane/ethyl acetate = 20:1): Rf = 0.59
(hexane/ethyl acetate = 2:1); mp 58–60 °C; 1H NMR (270 MHz,
CDCl3) d = 7.35–7.25 (m, 2H), 7.11–7.01 (m, 6H), 4.13–3.99 (m,
2H), 3.95–3.81 (m, 4H), 3.49 (d, J = 15.0 Hz, 2H), 3.38 (d,
J = 15.0 Hz, 2H), 2.16 (s, 6H), 1.80–1.66 (m, 2H), 0.94 (d,
J = 6.6 Hz, 6H), 0.84 (d, J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d = 167.1, 137.6, 136.1, 130.2, 129.7, 126.3, 125.4, 72.1, 69.9, 47.9,
35.8, 32.6, 20.1, 19.2, 18.0; IR (neat) mmax 2960, 2906, 1651, 1463,
1195, 1178, 1055, 1022, 1010, 962, 948, 899, 755, 742 cmꢀ1; HRMS
(FAB) [M+H]+ calculated for C29H39N2O2: 447.3012, found:
This compound was prepared from 17n by Procedure B as de-
scribed. A white solid (40%) was obtained after purification by silica
gel chromatography (hexane/ethyl acetate = 10:1): Rf = 0.53 (hex-
ane/ethyl acetate = 4:1); mp 114–116 °C; 1H NMR (270 MHz,
CDCl3); d = 7.29–7.24 (m, 4H), 7.22–7.16 (m, 4H), 4.25–4.09 (m,
2H), 3.95–3.79 (m, 4H), 3.37 (d, J = 14.2 Hz, 2H), 3.21 (d,
J = 14.2 Hz, 2H), 1.66–1.52 (m, 2H), 1.29 (s, 18H), 0.85 (d,
J = 6.9 Hz, 6H), 0.77 (d, J = 6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3);
d = 166.4, 149.3, 134.0, 130.3, 124.9, 72.1, 69.9, 48.3, 38.1, 34.4,
32.5, 31.5, 19.1, 18.0; IR (neat) mmax 2958, 2931, 2905, 2869, 1664,
1512, 1464, 1362, 1268, 1174, 1121, 1009, 981, 965, 840, 817,
600, 584 cmꢀ1; HRMS (FAB) [M+H]+ calculated for C35H51N2O2:
447.3021; ½a 2D0
¼ ꢀ91:5 (c 0.55, MeOH).
ꢁ
531.3951, found: 531.3961; ½a D20
¼ ꢀ59:5 (c0.43, MeOH).
ꢁ

356
T. Sawada, M. Nakada / Tetrahedron: Asymmetry 23 (2012) 350–356
4.3.9. (S)-4,5-Dihydro-2-(2-((S)-4,5-dihydro-4-isopropyloxazol-
2-yl)-1,3-bis(3,5-dimethylphenyl)propan-2-yl)-4-isopropylox-
azole 1o
min); retention time: 21.3 min for 16, 23.3 min for ent-16:
Rf = 0.35 (hexane/ethyl acetate = 1:1); mp = 114–115 °C (hexane/
CH2Cl2);
½
a 2D3:5
ꢁ
¼ ꢀ62:1 (c 0.60, CHCl3, 100% ee); 1H NMR
This compound was prepared from 17o by Procedure B as de-
scribed. A white solid (58%) was obtained after purification by sil-
ica gel chromatography (hexane/ethyl acetate = 10:1): Rf = 0.53
(hexane/ethyl acetate = 4:1); mp 82–84 °C; 1H NMR (270 MHz,
CDCl3) d = 6.84 (s, 6H), 4.24–4.08 (m, 2H), 3.97–3.81 (m, 4H),
3.31 (d, J = 13.9 Hz, 2H), 3.13 (d, J = 13.9 Hz, 2H), 2.26 (s, 12H),
1.75–1.61 (m, 2H), 0.90 (d, J = 6.6 Hz, 6H), 0.83 (d, J = 6.6 Hz, 6H);
13C NMR (125 MHz, CDCl3) d = 166.5, 137.1, 136.9, 128.6, 128.2,
72.2, 69.8, 48.3, 39.2, 32.7, 21.4, 19.1, 18.0; IR (neat) mmax 2956,
2927, 2871, 1662, 1605, 1463, 1366, 1240, 1188, 1175, 1162,
1032, 1011, 962, 950, 931, 890, 847, 697 cmꢀ1; HRMS (FAB)
[M+H]+ calculated for C31H43N2O2: 475.3325, found: 475.3325;
(400 MHz, CDCl3): d = 8.05 (d, J = 8.1 Hz, 2H), 7.65 (t, J = 7.3 Hz,
1H), 7.56 (dd, J = 8.1, 7.3 Hz, 2H), 3.09–3.01 (m, 1H), 2.33–2.15
(m, 4H), 2.10–1.96 (m, 1H), 1.54 (dd, J = 5.6, 3.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 203.2, 139.3, 133.6, 128.8, 128.6, 53.1,
33.6, 31.1, 20.5, 20.3; IR(KBr) mmax 1731, 1446, 1304, 1149,
1034 cmꢀ1
;
HRMS (FAB): [M+H]+ calculated for C12H13O3S
237.0585, found 237.0545.
Acknowledgments
This work was financially supported in part by a Waseda Uni-
versity Grant for Special Research Projects, a Grant-in-Aid for Sci-
entific Research on Innovative Areas (No. 21106009) and the
Global COE program ‘Center for Practical Chemical Wisdom’ by
MEXT.
½
a 2D0
ꢁ
¼ ꢀ89:4 (c 0.55, MeOH).
4.3.10. (S)-2-(1,3-Bis(3,5-di-tert-butylphenyl)-2-((S)-4,5-dihydro-
4-isopropyloxazol-2-yl)propan-2-yl)-4,5-dihydro-4-isopropyl-
oxazole 1p
References
This compound was prepared from 17p by Procedure B as de-
scribed. A white solid (17%) was obtained after purification by sil-
ica gel chromatography (hexane/ethyl acetate = 20:1): Rf = 0.73
(hexane/ethyl acetate = 4:1);mp 121–123 °C; 1H NMR (270 MHz,
CDCl3); d = 7.27–7.25 (m, 2H), 7.17–7.16 (m, 4H), 4.17–4.07 (m,
2H), 3.92–3.77 (m, 4H), 3.51 (d, J = 14.5 Hz, 2H), 3.28 (d,
J = 14.5 Hz, 2H), 1.66–1.50 (m, 2H), 1.29 (s, 36H), 0.85 (d,
J = 6.6 Hz, 6H), 0.76 (d, J = 6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3);
d = 166.6, 150.0, 136.3, 124.7, 120.6, 72.1,69.7, 48.1, 39.5, 34.8,
32.6, 31.7, 19.1, 17.7; IR (neat) mmax 2954, 2868, 1670, 1597,
1469, 1362, 1248, 1174, 1023, 1002, 965, 913, 897, 886, 875,
862, 714 cmꢀ1; HRMS (FAB) [M+H]+ calculated for C43H67N2O2:
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1544; (f) Watanabe, H.; Takano, M.; Nakada, M. J. Synth. Org. Chem. 2008, 66,
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643.5203, found: 643.5203; ½a D20
¼ ꢀ60:9 (c 0.47, MeOH).
ꢁ
4.4. The catalytic asymmetric intramolecular cyclopropanation
of 15 with ligand 1p
A
toluene azeotroped [CuOTf]2ꢂC6H6 (5.0 mg, 0.019 mmol,
10 mol % as CuOTf) was placed in a dried flask (10 mL) under an
Ar atmosphere and to this flask was added a solution of toluene
azeotroped ligand 1p (18.8 mg, 0.029 mmol, 15 mol %) in toluene
(0.5 mL ꢃ 2) via a cannula. The mixture was stirred at room tem-
perature for 0.5 h and then to the light blue solution was added a
solution of toluene azeotroped 1-diazo-1-phenylsulfonyl-5-hex-
ene-2-one 15 (50.0 mg, 0.189 mmol) in toluene (0.5 mL ꢃ 2) via a
cannula. The reaction mixture was stirred at room temperature
for 2 h, quenched with an NH4OH aqueous solution (1 mL), and ex-
tracted with ether (10 mL) and CH2Cl2 (10 mL ꢃ 2). The combined
organic layer was washed with brine (20 mL), dried over Na2SO4,
and evaporated. The residue was purified by preparative TLC (ben-
zene/ethyl acetate = 2:1) to afford (1R,5R)-1-phenylsulfonyl-2-
oxobicyclo[3.1.0]hexane 16 (31.1 mg, 70%, 81% ee) as a white solid.
Ee was determined by HPLC (254 nm); Daicel Chiral Cell OD-H
0.46 cm ꢃ 25 cm; hexane/isopropanol = 3:1; flow rate = 0.5 mL/
4. (a) Abe, M.; Nakada, M. Tetrahedron Lett. 2006, 47, 6347–6351; (b) Takeda, H.;
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P.; Kasture, S. P.; Aherwadkar, A. P.; Indian, J. Heterocycl. Chem. 2000, 10, 105–
108; Using ZnCl2, see: Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am.
Chem. Soc. 2001, 123, 8444–8445.
7. Seitz, M.; Capacchione, C.; Bellemin-Laponnaz, S.; Wadepohl, H.; Ward, B. D.;
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8. (a) Kang, H.-Y.; Hong, W. S.; Cho, Y. S.; Koh, H. Y. Tetrahedron Lett. 1995, 36,
7661–7664; (b) Tsai, T.-Y.; Shia, K.-S.; Liu, H.-J. Synlett 2003, 97–101.
9. Hodgson, D. M.; Lee, G. P.; Marriott, R. E.; Thompson, A. J.; Wisedale, R.;
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