Bisoxazoline ligands with an axial-unfixed biaryl backbone: the effects of the biaryl backbone and the substituent at oxazoline ring on Cu-catalyzed asymmetric cyclopropanation

Article abstract of DOI:10.1016/j.tetasy.2006.02.014

The synthesis of novel C₂-symmetric bisoxazoline ligands with an axial-unfixed biaryl backbone and different substituents at the oxazoline ring is reported. The diastereomer equilibrium of these ligands in solution and their complexation behavi

Full text of DOI:10.1016/j.tetasy.2006.02.014

Tetrahedron: Asymmetry 17 (2006) 767–777
Bisoxazoline ligands with an axial-unfixed biaryl backbone:
the effects of the biaryl backbone and the substituent at
oxazoline ring on Cu-catalyzed asymmetric cyclopropanation
Wanbin Zhang,a,* Fang Xie,a Shigeaki Matsuo,b Yuji Imahori,b Toshiyuki Kida,b
Yohji Nakatsujib and Isao Ikedab,*
aSchool of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
bDepartment of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Received 29 December 2005; accepted 10 February 2006
Available online 24 March 2006
Abstract—The synthesis of novel C2-symmetric bisoxazoline ligands with an axial-unfixed biaryl backbone and different substituents
at the oxazoline ring is reported. The diastereomer equilibrium of these ligands in solution and their complexation behavior with the
copper(I) ion were studied. Their application in Cu-catalyzed cyclopropanation of styrene, with diazoacetate, was carried out and
the effects of the biaryl backbone and the substituent on the oxazoline ring in the catalysis were examined. The best result was
obtained with the ligand having a 1,10-binaphthyl backbone and a t-butyl group on the oxazoline ring, which afforded 89% de
and 96% de for the trans- and cis-products of the above asymmetric cyclopropanation reaction, respectively.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
aration, complexation and application of novel C2-sym-
metric bisoxazoline ligands 2–4 with a biaryl backbone,
such as, 2,20-binaphthyl and a 5,50-disubstituted 1,10-
biphenyl. Here the axis around the carbon–carbon bond
between the two aryl rings is unfixed although a high
activation barrier should be expected. We report also the
preparation, complexation and application of novel C2-
symmetric biphenyl bisoxazoline ligands. We report 5–7
Over the last decade, chiral oxazoline ligands derived
from readily available amino acids, have found wide-
spread use in metal-catalyzed asymmetric reactions.1
We also prepared novel oxazoline ligands with a chiral
backbone, such as 1,3-dioxolane,2 ferrocene,3 and bia-
ryl4 moiety for the purpose of the development of effec-
tive asymmetric catalytic systems during recent years. By
the introduction of the chiral backbone, the asymmetric
induction by these ligands could be effectively controlled
by a combination of the substituent on the oxazoline
ring and the chiral backbone. Particularly, the oxazoline
ligands with a biaryl backbone have attracted much
attention and several other groups also developed this
kind of ligands, independently.5 However, one type of
our bisoxazoline ligands, such as 1 is different from oth-
ers,5 and has an axis-unfixed biphenyl backbone and the
two rotatory diastereomers of the ligand exist in equilib-
rium in solution.4a,c Upon complexation with a cop-
per(I) ion however, ligand 1 afforded only one of the
two possible complexes, which proved to be effective
for asymmetric catalysis.4a,c Herein, we report the prep-
R
R
O
O
N
N
N
N
O
O
R
R
1a: R=i-Pr
1b: R=t-Bu
2: R=t-Bu
Y
N
R
R
OR'
N
R
O
O
N
N
O
O
R
R
R'O
R
Y
a: R'=H
b: R'=Me
c: R'=Et
5: R=H
6: R=Me
7: R=Et
3: Y=Cl, R=t-Bu
4: Y=Ph, R=i-Pr
*
Corresponding authors. Tel./fax: 86 21 54743265 (W.Z.); e-mail
addresses: wanbin@sjtu.edu.cn; ikedaisa@estate.ocn.ne.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.014

768
W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
with substituents of different bulkiness on the oxazoline
ring.
a) NaNO2, NaOH,
then aq. HCl
Since these ligands were expected to have the same com-
plexation property as ligand 1, we planned to find the
best structure for this type of ligand with an axis-unfixed
backbone through the investigation of the effects of the
backbone and the kind of the substituent on the oxazo-
line ring on enantioselectivity.
COOH
HOOC
b) Cu(I)
COOH
60%
NH2
8
H
N
t
-Bu
OH
O
2. Results and discussions
2.1. Ligand preparation
a) SOCl2
MesCl
2
O
b) (S)-t-leucinol,
Et3N, CH2Cl2
Et3N, CH2Cl2
HO
N
H
t-Bu
50%
81%
Ligand 2 was prepared from 3-amino-2-naphthoic acid
and (S)-t-leucinol with ease (Scheme 1). Thus, by the
diazotization of 3-amino-2-naphthoic acid with sodium
nitrite followed by the coupling reaction with a Cu(I)
reducing solution,6 2,20-binaphthyl-3,30-dicarboxylic
acid 8 was obtained in 60% isolated yield. Then, 3,30-
bis(4-(S)-t-butyloxazolinyl)-2,20-binaphthyl 2 was easily
prepared from the dicarboxylic acid 8 and (S)-t-leucinol
in 41% overall yield through the corresponding diamide
9 as the intermediate followed by the oxazoline ring
closure reaction using methanesulfonyl chloride and
triethylamine.3a
9
Scheme 1.
Ph
H
Ph
a) SOCl2
N
i-Pr
b) (S
)-valinol,
Et3N, CH2Cl2
O
COOH
HO
98%
12
5,50-Dichloro-2,20-bisoxazolinyl-1,10-biphenyl
3
was
Ph
prepared from 2-amino-4-chlorobenzoic acid and (S)-t-
leucinol by the same method as ligand 2 in 31% overall
yield through 5,50-dichloro-1,10-biphenyl-2,20-dicarbox-
ylic acid 10 and the corresponding diamide 11 as
intermediates.
a) s-BuLi, THF
MesCl
b) CF2BrCF2Br
O
i
NEt3, CH2Cl2
82%
42%
N
13
-Pr
Ph
N
Cl
OH
i-Pr
Cl
Ph
H
N
O
N
t-Bu
Cu
pyridine
O
O
COOH
Cl
O
O
HOOC
HO
N
Br
N
t-Bu
i
-Pr
70%
H
Ph
Cl
i-Pr
14
4
10
11
5,50-Diphenyl-2,20-bisoxazolinyl-1,10-biphenyl
4
was
Scheme 2.
prepared by a different method compared to that for
ligands 2 and 3 because the corresponding 4-phenyl-2-
aminobenzoic acid is commercially unavailable (Scheme
2). Thus, at first biphenyl oxazoline 13 was prepared
with ease from 4-phenylbenzoic acid as a starting mate-
rial through amide 12 as an intermediate. Then, ligand 4
was prepared through the intermediate 4-phenyl-2-
bromophenyloxazoline 14 by ortho-lithiation of 13 with
s-butyllithium followed by bromination with 1,1,2,2-
tetrafluoro-1,2-dibromoethane7 and coupling reaction
with active copper powder in pyridine successively.8
methanesulfonyl chloride in the presence of triethylamine
failed, and afforded an elimination product 16 in 68%
yield. However, the ring closure reaction can be carried
out successfully by using Burgess’ reagent [(methoxy-
carbonyl sulfamoyl)triethylammonium hydroxide inner
salt].9 Thus, a mixture of 15 and Burgess’ reagent in
THF was heated at reflux for 2 h to give bisoxazoline
17 in 84% yield. Reduction of 17 with LiAlH4 in THF
afforded 5a in 82% yield, while 6a and 7a were afforded
by the reaction of the bisoxazoline 17 with methyl- and
ethylmagnesium bromide in good yields, respectively.
Then the reaction of 5a, 6a, and 7a with sodium hydride
followed by alkylation with iodomethane and bromo-
ethane afforded 5b, 5c, 6b, 6c, and 7b, respectively.
Ligands 5–7 were prepared from achiral 2,20-biphenyldi-
carboxylic acid and L-serine methyl ester hydrochloride
(Scheme 3). Thus, a mixture of L-serine methyl ester
hydrochloride, triethylamine, and 2,20-biphenyldicarb-
oxylic acid dichloride prepared from 2,20-biphenyldi-
carboxylic acid and thionyl chloride in CH2Cl2 was
stirred at room temperature overnight to give amide 15
in 78% yield. An attempt at oxazoline ring closure using
2.2. Behavior of ligands in solution
As expected, all of ligands 2–7, except for 5, gave two
1
sets of signals in H NMR spectra and the ratio of the

W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
769
H
MeO2C
N
a) SOCl2
HO
HO2C
O
OH
O
b) L-serine methyl
ester hydrochloride,
NEt3, CH2Cl2
CO2H
N
H
CO2Me
15
78%
H
MeO2C
N
MesCl
O
O
Et3N, CH2Cl2
N
CO2Me
H
68%
16
O
O
O
S
MeO
N
NEt3
-
+
CO2Me
O
(Burgess' reagent)
LiAlH4
N
15
N
THF
THF
O
MeO2C
82%
84%
17
HO
R'O
H
H
H
H
O
O
NaH, R'X
N
N
O
N
OH
N
H
H
H
H
THF
O
~86%
OR'
5b: R'=Me
5a
5c: R'=Et
R'O
HO
R
R
R
R
O
O
RMgX
THF
NaH, R'X
THF
N
17
N
N
N
R
R
R
O
O
R
~79%
~82%
OR'
OH
6b: R=Me, R'=Me
6c: R=Me, R'=Et
7b: R=Et, R'=Me
6a: R=Me
7a: R=Et
Scheme 3.
Table 1. Temperature dependence of the ratio of the two diastereo-
mers of ligand 1b and 2a
two sets of signals changed depending on the tempera-
ture, showing that for these ligands, two rotatory diaste-
reomers also exist in equilibrium in solution as was seen
in the case of ligand 1. In the case of 5, the reason as to
why only one set of signals was observed remains un-
known. Furthermore, the dependence of the rotatory
diastereomer ratio of these ligands upon temperature
seems rather significant. Table 1 gives the diastereomeric
ratios of ligands 1b and 2 at different temperatures. At
around room temperature, both ligands 1b and 2 gave
about the same ratio. However, at ꢀ60 ꢁC, the ratio of
ligand 2 was about 2.3 times higher than that of ligand
1b, showing that the biaryl backbone of this type of
ligand has a large effect on the equilibrium. Furthermore,
while all the protons of 1b coalesced at 40 ꢁC, the pro-
tons of 2 did not coalesce even at 60 ꢁC. This result
shows that the activation barrier between the two diaste-
reomers of 2 is much higher than that of the correspond-
Temperature (ꢁC)
Major:minor
1b
2
ꢀ60
ꢀ30
0
26
40
4.4:1
2.8:1
2.4:1
2.2:1
10.1:1
7.9:1
4.0:1
2.7:1
b
—
60
2.2:1
a Determined by 1H NMR (400 MHz, CDCl3).
b All signals coalesced, respectively.
ing ligand 1b.10 This may be due to the additional steric
repulsion between the t-Bu group at oxazoline ring and
the 80-position proton at the naphthalene ring.

770
W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
2.3. Complexation behavior of ligands with copper(I) ion
acetate.1a,b,f,g,i,12 In order to examine the effect of the
axis-unfixed biaryl backbone and the kind of the substi-
tuent on the oxazoline ring on asymmetric catalysis
using this new kind of ligand, the Cu(I)-catalyzed asym-
metric cyclopropanation of styrene with diazoacetate
was carried out.
The complexation behavior of ligand 2 on mixing with a
copper(I) triflate benzene complex [Cu(I)OTf(C6H6)0.5
]
and copper(I) iodide in solution was examined. Since
the activation barrier between the two diastereomers
of 2 was much higher than that of the corresponding
ligand 1b, the inter-conversion rate between the two
diastereomers of 2 should be slower than that of 1b.
Furthermore, the complexation of ligand 1 with zinc(II)
iodide may be a kinetically controlled process.4c There-
fore, it was doubted whether this ligand could afford
only one of the two possible diastereomers on complex-
ation with Cu(I) ion such as the corresponding biphenyl
ligands 1. However, when a solution of ligand 2 in chlo-
roform-d was mixed with 1 equiv of the copper(I) triflate
benzene complex or copper(I) iodide at room tempera-
At first, the results when using ligands 2–4 are shown in
Table 2. It can be seen that all the ligands afford about
yields of around 49–67%. This result is about the same
with those with oxazoline ligands 14a,c and 205b having
a biaryl backbone and several other recent examples.12i,j
It can also be seen that the biaryl backbone has a large
effect not only on trans/cis selectivity but also on diaste-
reoselectivity, as does the substituent on the oxazoline
ring,4a,c,5b although the reason for this remains un-
known. Among ligands 2–4, ligand 2 having an axis-un-
fixed binaphthyl backbone gave the best result and the
trans- and cis-products were obtained in a ratio of 83/
17 and with up to 89% de and 96% de, respectively.
These results are better than those with the correspond-
ing biphenyl derivative 1.4a,c With ligand 2, the diaste-
reoselectivities are slightly lower but the trans/cis
selectivity is higher than those with the corresponding
axis-fixed binaphthyl derivative (aS)-20,5b which was
prepared from racemic 1,10-binaphthyl-2,20-dicarboxylic
acid using a diastereomeric separation procedure. This
result suggests that ligand 2 with an axis-unfixed 2,20-
binaphthyl backbone existing as a mixture of two diaste-
reomers in equilibrium in solution can be completely
transferred to an active catalyst which affords very high
diastereoselectivities and trans/cis selectivity for the
Cu(I)-catalyzed asymmetric cyclopropanation of olefin
with diazoacetate.
1
ture, the H NMR spectra of the solution showed that
only one diastereomer was formed. The configuration
of the complex generated was deduced to be (aS)-18
(Scheme 4), because the axis chirality of the correspond-
ing complex of ligands 1 was assigned to be (aS).4c
The complexation behavior of ligands 5–7 having an
oxygen atom in the substituent at the oxazoline ring
on mixing with copper(I) triflate and iodide was next
examined. With copper(I) iodide, all of these ligands
were clearly proven to afford only one kind of the C2-
1
symmetric complex from H NMR. With copper(I) tri-
flate, all of these ligands also afford only one kind of
the C2-symmetric complex besides ligands 5a, 6a, and
7a having hydroxyl groups, which gave broad signals
1
in H NMR spectra on complexation, perhaps due to
the low solubility of the complexes in the solution.11
From the little difference in the chemical shifts of the
alkoxyl groups of the complex and those of the ligand
in 1H NMR spectra, it can be concluded that the oxygen
atom in the substituent at oxazoline ring does not coor-
dinate with the copper(I) ion. Therefore, the complexes
formed should be C2-symmetrically N,N0-coordinated,
the structure of which could be deduced to be (aR)-19.
(Note: the chirality at the oxazoline ring of this kind
of ligands is different from that of ligand 1.)
t-Bu
O
N
N
O
t-Bu
(aS)-20
The results with ligands 5–7 are shown in Table 3. It can
be seen that the type of R group on the oxazoline substi-
tuent has a large effect on catalytic activity. When the R
group is a proton, the yields are very high. However,
where the R group becomes larger, the yields become
lower. This may be caused by the hindrance of the large
R group for the approach of the substrate to the cop-
per(I) in the complex center. The R0 group of the ligand
has a large effect on catalytic activity also. When the R0 is
a proton, the yields are very low. This may be due to the
low solubility of the complexes in the solution.11 How-
ever, when the R0 group is a methyl or an ethyl group,
the yield becomes higher. The R and R0 groups of the
ligands also have a large effect on trans/cis selectivity
and diastereoselectivity. Amongst ligands 5–7, ligand
6b afforded the best result. This result is about the
same as that of ligand 1a with an i-Pr group at oxazo-
line ring but worse than that of ligand 1b with a t-Bu
group.
R
R'O
R
O
N
M
N
R
R
O
OR'
(aR
)-19
(R=H, Me, Et; R'=Me, Et; M=CuOTf, CuI)
2.4. Application in Cu(I)-catalyzed asymmetric
cyclopropanation
Cu(I)-catalyzed asymmetric cyclopropanation of olefin
with diazoacetate is attracting considerable attention
due to the demand for enantiomerically pure cyclopro-
panes, and some oxazoline ligands have been found to
be effective for cyclopropanation of styrene with diazo-

W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
771
t-Bu
t
-Bu
O
O
N
N
N
N
O
O
t
-Bu
t-Bu
(aS)-2
(aR)-2
-M
M
-M
M
t
-Bu
t-Bu
O
O
N
N
M
M
N
N
O
O
t
-Bu
t-Bu
(aR)-18
not found
(aS)-18
(M=CuOTf, CuI)
Scheme 4.
Table 2. Cu(I)-Catalyzed asymmetric cyclopropanation of styrene
with menthyldiazoacetatea
Table 3. Cu(I)-Catalyzed asymmetric cyclopropanation of styrene
with menthyldiazoacetatea
PhCH=CH2
PhCH=CH2
Ligand, CuOTf
Ligand, CuOTf
*
*
*
*
+
+
Ph
COOR
Ph
COOR
CH2Cl2
CH2Cl2
N2CHCOOR
N2CHCOOR
(R=
D
- or
L
-menthyl)
(R=
L-menthyl)
Ligand Yieldb (%) Trans/cisc
% dec
Cis (1R,2S)d Trans (1R,2R)d
Ligand Menthyl Yieldb (%) Trans/cisc
% dec (config.)d
Cis
Trans
1a
1b
2
60
60
49
67
62
79/21
81/19
83/17
62/38
92/8
87
92
96
90
53
97
70
84
89
70
40
95
5a
5b
5c
6a
6b
6c
7a
7b
1a
1b
D
D
D
D
D
D
D
D
L
48
80
78
21
69
66
15
31
60
60
95/5
92/8
0
15 (1S,2S)
27 (1S,2R) 3 (1S,2S)
20 (1S,2R) 3 (1R,2R)
88 (1S,2R) 69 (1S,2S)
90 (1S,2R) 63 (1S,2S)
81/19
83/17
87/13
78/22
84/16
75/25
79/21
81/19
3
4
(aS)-20e 50
68/32
23 (1S,2R)
0
a Conducted at 20 ꢁC with ligand (17 lmol), Cu(I)OTf(C6H6)0.5
(13 lmol), styrene (1.0 mmol), and menthyl diazoacetate (1.3 mmol)
in CH2Cl2 (2.0 mL) for 24 h.
83 (1S,2R) 77 (1S,2S)
43 (1S,2R) 25 (1S,2S)
87 (1R,2S) 70 (1R,2R)
92 (1R,2S) 84 (1R,2R)
b Isolated yield of a mixture of trans- and cis-product.
c Determined by GC.
L
a Conducted at 20 ꢁC with ligand (17 lmol), Cu(I)OTf(C6H6)0.5
(13 lmol), styrene (1.0 mmol), and menthyl diazoacetate (1.3 mmol)
in CH2Cl2 (2.0 mL) for 24 h.
d Determined by comparison of the specific rotation of their corre-
sponding ethyl ester with the literature.13
e See, Ref. 5b.
b Isolated yield of a mixture of trans- and cis-product.
c Determined by GC.
d Determined by comparison of the specific rotation of the corre-
sponding ethyl ester with the literature.13
3. Conclusion
We have prepared several new types of C2-symmetric
bisoxazoline ligands with an axis-unfixed biaryl back-
bone and different substituents at oxazoline ring. These
ligands were proven to exist as a mixture of two diaste-
reomers with opposite axial chirality in equilibrium in
solution and upon coordination with copper(I) ion only
one of the two possible rotatory diastereomer complexes
formed. These ligands were applied to the Cu-catalyzed
cyclopropanation of styrene with diazoacetate, and the
effects of the biaryl backbone and the kind of the substi-
tuent at oxazoline ring on the catalysis were examined.
The best result was obtained with the ligand having a
2,20-binaphthyl backbone and a t-butyl group at oxazo-
line ring, which afforded 89% de and 96% de for the

772
W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
trans- and cis-products of the above asymmetric cyclo-
propanation reaction, respectively.
was dried with magnesium sulfate and the solvent
removed under reduced pressure. The residue was puri-
fied by column chromatography with ethyl acetate and
then acetone as eluent to afford 2,20-binaphthyl-3,30-
dicarboxylic acid 8 (0.53 g, 1.6 mmol, 60%). Rf = 0.29
4. Experimental
1
(ethyl acetate). H NMR (400 MHz, CD3OD): d 7.56
Melting points were measured on a Yanagimoto micro-
melting point apparatus and are uncorrected. Optical
rotations were measured on a DIP-181 digital polari-
meter. 1H NMR spectra were recorded on a JEOL
GSX-400 spectrometer and the chemical shifts were ref-
erenced to CHCl3 (d 7.27) in CDCl3. The fast atom
bombardment mass spectra (FAB-MS) and high-resolu-
tion mass spectra (HRMS) were obtained on a JEOL
JMS-DX303HF spectrometer.
(dt, 2H, J 1.5, 7.6 Hz), 7.61 (dt, 2H, J 1.5, 7.6 Hz),
7.75 (s, 2H), 7.90 (br d, 2H, J 8.1 Hz), 8.01 (br d, 2H,
J 8.1 Hz), 8.60 (s, 2H). FABMS (m/z) 341 ([MꢀH]ꢀ).
4.2. 3,30-Bis{N-[(10S)-tert-butyl-20-hydroxyethyl]carbox-
amido}-2,20-binaphthyl 9
A mixture of 8 (0.53 g, 1.6 mmol) and thionyl chloride
(10.0 mL, 16.3 g, 137 mmol) was refluxed for 6 h. Low
boiling point chemicals were removed under reduced
pressure and the residue dissolved in dichloromethane
(5.0 mL). This solution was added to a solution of (S)-
tert-leucinol (0.41 g, 3.5 mmol) and triethylamine
(1.3 mL, 0.94 g, 9.3 mmol) in dry dichloromethane
(20 mL) dropwise at 0 ꢁC over 15 min. After being stir-
red for 3 h at room temperature, the resulting mixture
was washed with water and then brine, dried over mag-
nesium sulfate, and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography with ethyl acetate as eluent to give 9
(0.72 g, 1.3 mmol, 81%) as a light orange solid. Rf =
THF was freshly distilled from sodium, dichlorometh-
ane from P2O5, and DMF, TMEDA, and triethylamine
from CaH2 before use. All of the other chemicals used in
synthetic procedures were of reagent grade. Merck 70–
230 mesh silica gel was used for column chromatogra-
phy. TLC plastic sheet (Silica gel 60 F254) was used
for the determination of Rf. All of the reactions were
carried out under an argon atmosphere.
4.1. 2,20-Binaphthyl-3,30-dicarboxylic acid 8
1
4.1.1. Diazotization of 3-amino-2-naphthoic acid. 3-
Amino-2-naphthoic acid (1.00 g, 5.34 mmol) was dis-
solved in a solution of sodium hydroxide (0.28 g,
7.0 mmol) in water (12.5 mL). To this solution was
added sodium nitrite (0.44 g, 6.4 mmol) and the solution
cooled to 10 ꢁC. Then, this solution was added to a solu-
tion of concentrated hydrochloric acid (1.8 mL) and
water (3.6 mL) at 10 ꢁC for 2 h with efficient stirring to
give a diazo solution.
0.42 (ethyl acetate). The H NMR of 9 shows two sets
of signals in CDCl3 (52/48). 1H NMR (400 MHz,
CDCl3) major: d 0.67 (s, 18H); minor: d 0.80 (s, 18H).
The other signals are overlapped.
4.3. 3,30-Bis[(40S)-tert-butyloxazolin-20-yl]-2,20-binaph-
thyl 2
To a solution of 9 (0.49 g, 0.91 mmol) and triethylamine
(0.75 mL, 0.55 g, 5.4 mmol) in dry dichloromethane
(25 mL) was added methanesulfonyl chloride (0.15 mL,
0.22 g, 1.9 mmol) dropwise by syringe for 5 min at
0 ꢁC. After being stirred overnight at room temperature,
the resulting mixture was washed with water and then
brine, dried over magnesium sulfate, and then concen-
trated under reduced pressure. The residue was purified
by silica gel column chromatography with ethyl acetate/
hexane (1/4) as eluent to give 2 (0.23 g, 0.46 mmol, 50%)
as a light orange solid. Rf = 0.27 (ethyl acetate/hexane =
4.1.2. Preparation of the reducing agent. Cupric sulfate
pentahydrate (2.80 g, 11.2 mmol) was dissolved in water
(9.0 mL) and then concentrated ammonium hydroxide
(28%, 4.7 mL) was added with stirring and the solution
cooled to 10 ꢁC. To a solution of hydroxylamine hydro-
chloride (0.86 g, 12 mmol) in water (2.5 mL) was added
6 M sodium hydroxide solution (1.7 mL, 10 mmol) at
10 ꢁC. This hydroxylamine solution was immediately
added to the ammoniacal cupric sulfate solution with
stirring. Reduction occurred at once with the evolution
of nitrogen, and the solution becomes pale blue.
1
1/4). The H NMR of 2 shows two sets of signals in
CDCl3 (91/9, ꢀ60 ꢁC). 1H NMR (400 MHz, CDCl3,
ꢀ60 ꢁC) major: d 0.92 (s, 18H), 3.56 (t, 2H, J 8.8 Hz),
3.96 (t, 2H, J 9.9 Hz), 4.15 (t, 2H, J 9.2 Hz), 7.57 (m,
4H), 7.76 (m, 2H), 7.80 (s, 2H), 7.95 (m, 2H), 8.46 (s,
2H); minor: d 0.80 (s, 18H), 3.83 (m, 2H), 3.92 (m,
2H), 4.00 (m, 2H), 7.35–8.00 (m, 8H), 7.83 (s, 2H),
4.1.3. The coupling of the diazotized 3-amino-2-naphthoic
acid. The reducing solution prepared above was cooled
to 10 ꢁC and maintained at 10–15 ꢁC during the addition
of the diazo solution, which is added by a syringe with
the needle dipping well below the surface of the reducing
solution. The diazo solution was added for 1 h and a lot
of foaming occurred. After addition, the solution was
stirred for an additional 5 h. The solution was heated
to 80 ꢁC, and rapidly acidified with concentrated hydro-
chloric acid with vigorous stirring. At this point acidifi-
cation was continued more carefully until the solution
was acid to Congo Red. The solution was allowed to
stand overnight. The solid was filtered by suction and
dissolved in ethyl acetate. The ethyl acetate solution
8.43 (s, 2H). HRMS(EI) calcd for C34H36N2O2:
9
504.2818, found 504.2790. Mp: 73–76 ꢁC. ½aꢁD ¼ ꢀ78:5
(c 0.50, CHCl3).
4.4. 5,50-Dichloro-1,10-biphenyl-2,20-dicarboxylic acid 10
Following a procedure identical to that described for
the preparation of 8, 10 (6.60 g, 21.2 mmol, 73%) was
prepared from 2-amino-4-chlorobenzoic acid (10.0 g,
58.3 mmol) as a light yellow solid. Rf = 0.42 (acetone/

W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
773
hexane = 4/1). 1H NMR (400 MHz, CD3OD): d 7.18 (d,
2H, J 2.2 Hz), 7.45 (dd, 2H, J 2.2, 8.4 Hz), 7.90 (d, 2H, J
8.4 Hz). IR (KBr, cmꢀ1) 1531, 1633, 3236. FABMS (m/z)
310 (M+).
1.45 g, 13 mmol) in the presence of triethylamine
(5.9 mL, 4.3 g, 42 mmol). Rf = 0.25 (ethyl acetate/hex-
ane = 1/3). 1H NMR (400 MHz, CDCl3): d 0.96 (d,
3H, J 6.6 Hz), 1.06 (d, 3H, J 7.0 Hz), 1.90 (m, 1H),
4.11–4.20 (m, 2H), 4.44 (m, 1H), 7.38 (tt, 1H, J 1.5,
7.3 Hz), 7.47 (m, 2H), 7.64 (m, 4H), 8.03 (td, 2H, J
1.8, 8.4 Hz). FABMS (m/z) 266 ([M+1]+).
4.5. 5,50-Dichloro-2,20-bis{N-[(10S)-tert-butyl-20-
hydroxyethyl]carboxamido}-1,10-biphenyl 11
Following a procedure identical to that described for the
preparation of 9, 11 (1.90 g, 3.73 mmol, 89%) was pre-
pared from 10 (1.30 g, 4.18 mmol) as a light yellow solid.
Rf = 0.35 (ethyl acetate). The 1H NMR of 11 shows two
4.9. 3-Bromo-4-[(40S)-isopropyloxazolin-20-yl]-1,10-bi-
phenyl 14
To a solution of 13 (1.00 g, 3.77 mmol) in dry THF
(40 mL) was added dropwise over 10 min, a solution
of s-butyllithium in hexane (1.0 M, 4.6 mL, 4.6 mmol)
at ꢀ78 ꢁC. After being stirred at this temperature for
3 h, a solution of 1,2-dibromotetrafluoroethane (0.92
mL, 2.0 g, 7.7 mmol) in dry THF (20 mL) was added
to the mixture dropwise over 15 min. The mixture was
stirred at ꢀ78 ꢁC for an additional 1 h and overnight
at room temperature. Then, the mixture was concen-
trated under reduced pressure and residue was dissolved
in dichloromethane (100 mL). The solution was washed
with water and brine, dried over magnesium sulfate, and
then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography with
ethyl acetate/hexane (1/5) as eluent to give 14 (0.54 g,
1.6 mmol, 42%) as a light yellow oil. Rf = 0.30 (ethyl
1
sets of signals in CDCl3 (51/49). H NMR (400 MHz,
CDCl3) major: d 0.75 (s, 18H), 3.30 (dd, 2H, J 8.1,
11.4 Hz), 3.66 (dd, 2H, J 3.7, 11.4 Hz), 3.79 (m, 2H),
7.09 (br, 2H), 7.22 (d, 2H, J 2.2 Hz), 7.40 (m, 2H),
7.60 (d, 2H, J 8.1 Hz); minor : d 0.89 (s, 18H), 3.48
(dd, 2H, J 7.5, 11.5 Hz), 3.72 (dd, 2H, J 3.7, 11.4 Hz),
3.79 (m, 2H), 7.20 (br, 2H), 7.24 (d, 2H, J 2.2 Hz),
7.40 (m, 2H), 7.50 (d, 2H, J 8.1 Hz). FABMS (m/z)
509 ([MꢀH]ꢀ).
4.6. 5,50-Dichloro-2,20-bis[(40S)-tert-butyloxazolin-20-yl]-
1,10-biphenyl 3
Following a procedure identical to that described for the
preparation of 2, 3 (0.14 g, 0.29 mmol, 48%) was pre-
pared from 11 (0.31 g, 0.61 mmol) as a light yellow oil.
Rf = 0.49 (ethyl acetate/hexane = 1/2). The 1H NMR
of 2 shows two sets of signals in CDCl3 (75/25,
1
acetate/hexane = 1/5). H NMR (400 MHz, CDCl3):
d1.01 (d, 3H, J 7.0 Hz), 1.08 (d, 3H, J 7.0 Hz), 1.94
(m, 1H), 4.20 (m, 2H), 4.46 (m, 1H), 7.41 (m, 1H),
7.47 (m, 2H), 7.58 (m, 3H), 7.77 (d, 1H, J 8.1 Hz),
7.88 (d, 1H, J 1.8 Hz).
1
ꢀ60 ꢁC). H NMR (400 MHz, CDCl3, ꢀ60 ꢁC) major:
d 0.87 (s, 9H), 3.72 (m, 2H), 3.89 (t, 2H, J 9.9 Hz),
4.15 (t, 2H, J 9.5 Hz), 7.18 (d, 2H, J 1.8 Hz), 7.37 (dd,
2H, J 1.8, 8.4 Hz), 7.79 (d, 2H, J 8.4 Hz); minor: d
0.73 (s, 18H), 3.88 (m, 2H), 4.02 (m, 2H), 4.09 (q, 2H,
J 7.3 Hz), 7.15 (d, 2H, J 2.2 Hz), 7.34 (dd, 2H, J 2.2,
4.10. 5,50-Diphenyl-2,20-bis[(40S)-isopropyloxazolin-20-
yl]-1,10-biphenyl 4
8.4 Hz), 7.82 (d, 2H, J 8.4 Hz). HRMS(EI) calcd for
13
C26H30Cl2N2O2: 472.1687, found 472.1682. ½aꢁD
¼
A mixture of 14 (97 mg, 0.28 mmol) and freshly acti-
vated copper (47 mg, 0.73 mmol) in dry pyridine
(1.5 mL, 19 mmol) was heated at reflux for 12 h. After
being cooled, the mixture was diluted with dichloro-
methane (30 mL) and washed with 25% aqueous ammo-
nia (20 mL). The ammonia layer was extracted with
dichloromethane twice (20 mL · 2). The organic layers
were combined and washed with brine (50 mL). The
brine layer was extracted with dichloromethane twice
(40 mL · 2) and the combined organic layers were dried
over magnesium sulfate, and then concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography with ethyl acetate/hexane (1/
3) as eluent to give 4 (52 mg, 0.098 mmol, 70%) as an
yellow oil. Rf = 0.10 (ethyl acetate/hexane = 1/3). The
1H NMR of 4 shows two sets of signals in CDCl3 (65/
35). 1H NMR (400 MHz, CDCl3) major: d 0.78 (d,
6H, J 6.6 Hz), 0.82 (d, 6H, J 6.6 Hz), 1.70 (m, 2H),
3.77 (t, 2H, J 8.1 Hz), 3.89 (m, 2H), 4.17 (m, 2H),
7.34–7.48 (m, 6H), 7.54 (m, 2H), 7.60–7.71 (m, 6H),
7.95 (br d, 2H, J 8.1 Hz); minor: d 0.78 (d, 6H, J
6.6 Hz), 0.83 (d, 6H, J 6.6 Hz), 1.64 (m, 2H), 3.90 (m,
4H), 4.06 (m, 2H), 7.34–7.48 (m, 6H), 7.54 (m, 2H),
7.60–7.71 (m, 6H), 8.01 (br d, 2H, J 8.1 Hz). HRMS(EI)
ꢀ96:6 (c 0.50, CHCl3).
4.7. 4-{N-[(10S)-Isopropyl-20-hydroxyethyl]carbox-
amido}-1,10-biphenyl 12
Following a procedure identical to that described for the
preparation of 9, 12 (7.00 g, 24.7 mmol, 98%) was pre-
pared as a white solid from 4-biphenylcarboxylic acid
(5.00 g, 25.2 mmol) with 4-biphenylcarbonyl chloride
as intermediate followed by reaction with (S)-valinol
(3.60 g, 35.0 mmol) in the presence of triethylamine
1
(11.0 mL, 8.0 g, 79 mmol). Rf = 0.43 (ethyl acetate). H
NMR (400 MHz, CDCl3): d 1.06 (d, 3H, J 6.6 Hz),
1.07 (d, 3H, J 7.0 Hz), 2.06 (m, 1H), 3.84 (m, 2H),
3.99 (m, 1H), 6.38 (d, 1H, J 7.7 Hz), 7.40 (tt, 1H, J
1.3, 7.3 Hz), 7.48 (tt, 2H, J 1.5, 7.3 Hz), 7.62 (m, 2H),
7.68 (td, 2H, J 1.8, 8.4 Hz), 7.87 (td, 2H, J 1.8,
8.4 Hz). FABMS (m/z) 284 ([M+1]+).
4.8. 4-[(40S)-Isopropyloxazolin-20-yl]-1,10-biphenyl 13
Following a procedure identical to that described for the
preparation of 2, 13 (2.30 g, 8.67 mmol, 82%) was pre-
pared as a white solid by the reaction of 12 (3.00 g,
10.6 mmol) with methanesulfonyl chloride (0.98 mL,
calcd for C36H36N2O2: 528.2779, found 528.2756.
13
½aꢁD ¼ ꢀ59:0 (c 0.50, CHCl3).

774
W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
4.11. 2,20-Bis{N-[(10S)-methoxycarbonyl-20-hydroxy-
4.13. 2,20-Bis[(40R)-(hydroxymethyl)oxazolin-20-yl]-1,10-
biphenyl 5a
ethyl]carboxamido}-1,10-biphenyl 15
Following a procedure identical to that described for the
preparation of 9, 15 (7.10 g, 16.0 mmol, 78%) was pre-
pared as a light yellow solid from 2,20-biphenyldicarb-
A solution of 17 (1.10 g, 2.69 mmol) in THF (50 mL)
was added dropwise over 15 min to a suspension of
LiAlH4 (0.30 g, 7.9 mmol) in THF (40 mL) at ꢀ10 ꢁC.
The reaction mixture was stirred further for 2 h at this
temperature and overnight at room temperature. Ethyl
acetate (2 mL) was added to the mixture. After being
stirred for several minutes, the solvent was evaporated.
The residue was dissolved in dichloromethane (100
mL). The solution was washed with brine (30 mL), dried
over sodium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography with acetone as eluent to give 5a
(0.79 g, 2.2 mmol, 82%) as a white solid. Rf = 0.27 (ace-
tone). The 1H NMR of 5a shows only one set of signals
in CDCl3. 1H NMR (400 MHz, CDCl3): d 3.38 (m, 2H),
3.91 (t, 2H, J 8.0 Hz), 4.06–4.23 (m, 6H), 7.39–7.46 (m,
4H), 7.51–7.58 (m, 4H). FABMS (m/z) 353 ([M+1]+).
oxylic
acid
(5.00 g,
20.6 mmol)
with
2,20-
biphenyldicarbonyl chloride as intermediate followed
by reaction with L-serine methyl ester hydrochloride
(8.10 g, 52.1 mmol) in the presence of triethylamine
(17.0 mL, 12.3 g, 122 mmol). Rf = 0.15 (ethyl acetate).
1
The H NMR of 15 shows two sets of signals in CDCl3
1
(69/31). H NMR (400 MHz, CDCl3) major: d 3.68 (s,
6H), 3.80 (m, 2H), 4.02 (t, 2H, J 7.0 Hz), 4.11 (m,
2H), 4.42 (m, 2H), 6.36 (d, 2H, J 5.1 Hz), 7.48 (dd,
2H, J 1.5, 7.7 Hz), 7.56 (dt, 2H, J 1.5, 7.7 Hz), 7.70
(dt, 2H, J 1.5, 7.7 Hz), 7.85 (dd, 2H, J 1.5, 7.7 Hz); min-
or: d 3.59 (m, 2H), 3.76 (s, 6H), 3.78 (m, 2H), 4.14 (m,
2H), 4.59 (m, 2H), 7.31–7.38 (m, 4H), 7.43–7.54 (m,
4H), 7.69 (dt, 2H, J 1.5, 7.7 Hz). FABMS (m/z) 445
([M+1]+).
HRMS(EI) calcd for C20H20N2O4: 352.1424, found
9
352.1422. ½aꢁD ¼ þ53:4 (c 0.51, CHCl3).
4.12. 2,20-Bis [(40S)-(methoxycarbonyl)oxazolin-20-yl]-
1,10-biphenyl 17
4.14. 2,20-Bis[(40R)-(methoxymethyl)oxazolin-20-yl]-1,10-
biphenyl 5b
4.12.1. Attempted oxazoline ring closure of 15 using
methanesulfonyl chloride. Following a procedure iden-
tical to that described for the preparation of 2, 17 was
not obtained by the reaction of 15 (0.55 g, 1.2 mmol)
with methanesulfonyl chloride (0.25 mL, 0.37 g, 3.2 mmol)
in the presence of triethylamine (1.8 mL, 1.3 g, 13 mmol).
However, an elimination product, 2,20-bis{N-[10-(meth-
oxycarbonyl)vinyl]carboxamido}-1,10-biphenyl 16, was
obtained as a light yellow solid by this reaction
(0.33 g, 0.81 mmol, 68%). Rf = 0.27 (ethyl acetate/hex-
ane = 1/1). 1H NMR (400 MHz, CDCl3): d 3.80 (s,
6H), 5.85 (d, 2H, J 2.0 Hz), 6.55 (s, 2H), 7.20 (m, 2H),
7.45 (m, 4H), 7.70 (m, 2H), 8.60 (s, 2H). FABMS (m/z)
409 ([M+1]+).
A solution of 5a (50 mg, 0.14 mmol) in THF (1.0 mL)
was added to a suspension of NaH (29 mg, 60% in
nujol, 0.73 mmol) in THF (1.0 mL) at 0 ꢁC. After being
stirred for several minutes, iodomethane (44 lL,
0.10 g, 0.71 mmol) was added and the reaction mixture
stirred at room temperature overnight. The solvent
was evaporated and the residue dissolved in dichloro-
methane (20 mL). The solution was washed with water
(10 mL) and brine (10 mL), dried over sodium sulfate,
and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography with
acetone as eluent to give 5b (46 mg, 0.12 mmol, 86%)
1
as a colorless viscous oil. Rf = 0.36 (acetone). The H
NMR of 5b shows two sets of signals in CDCl3 at
1
4.12.2. Oxazoline ring closure of 15 using Burgess’
reagent. A solution of 15 (6.00 g, 13.5 mmol) and Bur-
gess’ reagent [(methoxycarbonylsulfamoyl)triethylam-
monium hydroxide inner salt] (6.70 g, 28.1 mmol) in
THF (200 mL) was refluxed for 2.5 h. The solvent was
evaporated and the residue was dissolved in dichloro-
methane (200 mL). The solution was washed with water
(100 mL) and brine (100 mL), dried over sodium sul-
fate, and concentrated under reduced pressure. The res-
idue was purified by silica gel column chromatography
with ethyl acetate as eluent to give 17 (4.60 g,
11.3 mmol, 84%) as a colorless viscous oil. Rf = 0.25
0 ꢁC (72/28). H NMR (400 MHz, CDCl3, 0 ꢁC) major:
d 3.31 (dd, J 7.0, 9.5 Hz, 2H), 3.35 (s, 6H), 3.46 (dd, J
4.7, 9.5 Hz, 2H), 3.89 (t, J 7.8 Hz, 2H), 4.20 (dd, J 8.1,
9.5 Hz, 2H), 4.28 (m, 2H), 7.32 (dd, J 1.5, 8.0 Hz, 2H),
7.36–7.52 (m, 4H), 7.82 (dd, J 2.5, 7.7 Hz, 2H); minor:
d 3.25 (dd, J 7.6, 9.1 Hz, 2H), 3.34 (s, 6H), 3.51 (dd, J
5.2, 9.5 Hz, 2H), 3.98 (t, J 8.1 Hz, 2H), 4.11 (dd, J 7.3,
8.8 Hz, 2H), 4.28 (m, 2H), 7.25 (br d, 2H), 7.36–7.52
(m, 4H), 7.85 (m, 2H). HRMS(EI) calcd for
10
C22H24N2O4: 380.1737, found 380.1738. ½aꢁD ¼ þ150:5
(c 0.49, CHCl3).
1
(ethyl acetate). The H NMR of 17 shows two sets of
4.15. 2,20-Bis [(40R)-(ethoxymethyl)oxazolin-20-yl]-1,10-
biphenyl 5c
1
signals in CDCl3 (72/28). H NMR (400 MHz, CDCl3)
major: d 3.77 (s, 6H), 4.25 (m, 2H), 4.34 (t, 2H, J
8.4 Hz), 4.73 (m, 2H), 7.33 (br d, 2H, J 7.7 Hz), 7.41
(dt, 2H, J 1.5, 7.7 Hz), 7.54 (dt, 2H, J 1.5, 7.7 Hz),
7.88 (dd, 2H, J 1.5, 7.7 Hz); minor: d 3.74 (s, 6H),
4.24 (m, 2H), 4.37 (m, 2H), 4.74 (m, 2H), 7.25 (m,
2H), 7.39 (m, 2H), 7.48 (dt, 2H, J 1.5, 7.7 Hz), 7.92
(dd, 2H, J 1.5, 7.7 Hz). FABMS (m/z) 409 ([M+1]+).
HRMS(EI) calcd for C22H20N2O6: 408.1322, found
408.1318.
Following a procedure identical to that described for the
preparation of 5b, 5c (42 mg, 0.10 mmol, 77%) was ob-
tained from 5a (45 mg, 0.13 mmol) and bromoethane
(48 lL, 0.070 g, 0.64 mmol) as a colorless viscous oil.
1
Rf = 0.40 (acetone). The H NMR of 5c shows two sets
of signals in CDCl3 (64/36). 1H NMR (400 MHz,
CDCl3) major: d 1.16 (t, J 7.0 Hz, 6H), 3.29 (t, J
8.8 Hz, 2H), 3.42–3.59 (m, 6H), 3.90 (t, J 7.7 Hz, 2H),

W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
775
4.19 (t, J 8.8 Hz, 2H), 4.25 (m, 2H), 7.31 (br d, J 7.4 Hz,
2H), 7.37 (t, J 7.7 Hz, 2H), 7.47 (t, J 7.7 Hz, 2H), 7.81
(br d, J 7.7 Hz, 2H); minor: d 1.16 (t, J 7.0 Hz, 6H),
3.23 (t, J 8.8 Hz, 2H), 3.42–3.59 (m, 6H), 3.98 (t, J
8.1 Hz, 2H), 4.10 (t, J 8.5 Hz, 2H), 4.26 (m, 2H), 7.24
(br d, J 7.7 Hz, 2H), 7.30–7.49 (m, 4H), 7.83 (br d, J
two sets of signals in CDCl3 (72/28). 1H NMR
(400 MHz, CDCl3) major: d 0.88 (s, 6H), 1.08 (t, J
7.0 Hz, 6H), 1.17 (s, 6H), 3.34 (m, 4H), 3.96–4.18 (m,
6H), 7.28 (br d, 2H), 7.34–7.45 (m, 4H), 7.83 (br d, J
7.7 Hz, 2H); minor: d 0.86 (s, 6H), 1.08 (t, J 7.0 Hz,
6H), 1.15 (s, 6H), 3.38 (m, 4H), 3.96–4.18 (m, 6H),
7.19 (br d, J 7.7 Hz, 2H), 7.34–7.45 (m, 4H), 7.88 (br
d, J 7.7 Hz, 2H). FABMS (m/z) 465 ([M+1]+).
7.7 Hz, 2H). HRMS(EI) calcd for C24H28N2O4:
9
408.2050, found 408.2065. ½aꢁD ¼ þ116:4 (c 0.51,
CHCl3).
HRMS(EI) calcd for C28H36N2O4: 464.2677, found
10
464.2672. ½aꢁD ¼ þ102:8 (c 0.50, CHCl3).
4.16. 2,20-Bis[(40S)-(dimethylhydroxylmethyl)oxazolin-20-
yl]-1,10-biphenyl 6a
4.19. 2,20-Bis[(40S)-(diethylhydroxylmethyl)oxazolin-20-
yl]-1,10-biphenyl 7a
A solution of methylmagnesium bromide in THF
(0.93 M, 3.3 mL, 3.1 mmol) was added dropwise over
10 min to a solution of 17 (0.21 g, 0.51 mmol) in dry
THF (10 mL) with stirring at 0 ꢁC. After stirring at
room temperature for 2 h, the solvent was removed
under reduced pressure. The residue was dissolved in
dichloromethane (50 mL). The solution was washed
with water (30 mL) and brine (30 mL), dried over
sodium sulfate, and concentrated under reduced pres-
sure. The residue was purified by silica gel column chro-
matography with ethyl acetate as an eluent to give 6a
(0.17 g, 0.42 mmol, 82%) as a colorless oil. Rf = 0.16
Following a procedure identical to that described for the
preparation of 6a, 7a (0.17 g, 0.37 mmol, 56%) was ob-
tained as a white solid from 17 (0.27 g, 0.66 mmol)
and a solution of ethylmagnesium bromide prepared
by stirring a mixture of magnesium (0.16 g, 6.6 mmol)
and bromoethane (0.55 mL, 0.80 g, 7.3 mmol) in THF
(5.0 mL) at room temperature for 30 min. Rf = 0.36
1
(ethyl acetate). The H NMR of 7a shows two sets of
1
signals in CDCl3 (70/30). H NMR (400 MHz, CDCl3):
major: d 0.74 (t, J 7.5 Hz, 6H), 0.85 (t, J 7.5 Hz, 6H),
1.25 (m, 4H), 1.35 (m, 4H), 4.01 (t, J 9.5 Hz, 2H), 4.15
(m, 2H), 4.23 (t, J 8.4 Hz, 2H), 7.33 (d, J 7.7 Hz, 2H),
7.39 (m, 2H), 7.52 (m, 2H), 7.75 (m, 2H); minor: d
0.71 (t, J 7.5 Hz, 6H), 0.78 (t, J 7.5 Hz, 6H), 1.19
(m, 4H), 1.61 (m, 4H), 3.85 (t, J 7.9 Hz, 2H), 4.11 (m,
4H), 7.26 (d, J 7.7 Hz, 2H), 7.39 (m, 2H), 7.46 (m,
2H), 7.75 (m, 2H). FABMS (m/z) 465 ([M+1]+).
1
(ethyl acetate). The H NMR of 6a shows two sets of
1
signals in CDCl3 (59/41). H NMR (400 MHz, CDCl3)
major: d 1.00 (s, 6H), 1.00 (s, 6H), 3.93 (m, 2H), 4.16
(m, 2H), 4.20 (m, 2H), 7.33–7.56 (m, 6H), 7.77 (br d, J
7.7 Hz, 2H); minor: d 0.85 (s, 6H), 1.26 (s, 6H), 3.91
(dd, J 3.3, 8.8 Hz, 2H), 4.02 (t, J 8.8 Hz, 2H), 4.15 (m,
2H), 7.25 (br d, J 7.7 Hz, 2H), 7.33–7.56 (m, 4H), 7.77
HRMS(CI) calcd for C28H37N2O4: 465.2755, found
27
(br d, J 7.7 Hz, 2H). HRMS(CI) calcd for C24H29-
465.2747. ½aꢁD ¼ þ83:7 (c 0.13, CHCl3).
27
N2O4: 409.2129, found 409.2117. ½aꢁD ¼ þ71:2 (c 0.70,
CHCl3).
4.20. 2,20-Bis[(40S)-(diethylmethoxymethyl)oxazolin-20-
yl]-1,10-biphenyl 7b
4.17. 2,20-Bis[(40S)-(dimethylmethoxymethyl)oxazolin-20-
yl]-1,10-biphenyl 6b
Following a procedure identical to that described for the
preparation of 5b, 7b (25 mg, 0.050 mmol, 51%) was ob-
tained from 7a (46 mg, 0.099 mmol) and iodomethane
(31 lL, 0.071 g, 0.50 mmol) as a colorless oil. Rf = 0.12
(ethyl acetate/hexane = 1/5). The 1H NMR of 7a shows
two sets of signals in CDCl3 (64/36). 1H NMR
(400 MHz, CDCl3) major: d 0.75–0.83 (m, 12H), 1.33–
1.57 (m, 8H), 3.12 (s, 6H), 4.03–4.20 (m, 6H), 7.28 (br
d, J 7.7 Hz, 2H), 7.33–7.46 (m, 4H), 7.82 (dd, J 1.5,
7.7 Hz, 2H); minor: d 0.75–0.83 (m, 12H), 1.33–1.57
(m, 8H), 3.08 (s, 6H), 4.03–4.20 (m, 6H), 7.17 (br d, J
7.7 Hz, 2H), 7.33–7.46 (m, 4H), 7.87 (dd, J 1.5, 7.7 Hz,
Following a procedure identical to that described for the
preparation of 5b, 6b (0.16 g, 0.37 mmol, 79%) was
obtained from 6a (0.19 g, 0.47 mmol) and iodomethane
(0.43 mL, 0.98 g, 6.9 mmol) as a white solid. Rf = 0.16
(ethyl acetate/hexane = 1/3). The 1H NMR of 6b shows
two sets of signals in CDCl3 (70/30). 1H NMR
(400 MHz, CDCl3) major: d 0.88 (s, 6H), 1.14 (s, 6H),
3.16 (s, 6H), 3.96–4.16 (m, 6H), 7.29 (br d, J 7.7 Hz,
2H), 7.35–7.47 (m, 4H), 7.84 (br d, J 7.7 Hz, 2H); minor:
d 0.86 (s, 6H), 1.13 (s, 6H), 3.16 (s, 6H), 3.96–4.16 (m,
6H), 7.19 (br d, J 7.7 Hz, 2H), 7.35–7.47 (m, 4H), 7.89
(br d, J 7.7 Hz, 2H). FABMS (m/z) 437 ([M+1]+).
2H). HRMS(CI) calcd for C30H41N2O4: 493.3147, found
9
493.3185. ½aꢁD ¼ þ67:4 (c 0.52, CHCl3).
HRMS(EI) calcd for C26H32N2O4: 436.2363, found
10
436.2363. ½aꢁD ¼ þ119:9 (c 0.50, CHCl3).
4.21. 3,30-Bis[(40S)-tert-butyloxazolin-20-yl]-2,20-binaph-
thyl copper(I) triflate complex (aS)-18, M = Cu(OTf)
4.18. 2,20-Bis[(40S)-(dimethylethoxymethyl)oxazolin-20-
yl]-1,10-biphenyl 6c
To a solution of ligand 2 (5.0 mg, 10 lmol) in chloro-
form-d (1.0 mL) was added 1 equiv of [Cu(I)OTf-
(C6H6)0.5] (2.6 mg, 10 lmol) and the suspension was stir-
red at room temperature under an argon atmosphere
Following a procedure identical to that described for the
preparation of 5b, 6c (46 mg, 0.099 mmol, 58%) was ob-
tained from 6a (68 mg, 0.17 mmol) and iodoethane
(0.14 mL, 0.27 g, 1.7 mmol) as a white solid. Rf = 0.27
1
until complete dissolution. The H NMR of this solu-
tion showed only one set of signals. (aS)-18 (M =
1
(ethyl acetate/hexane = 1/1). The H NMR of 6c shows
Cu(OTf)): 1H NMR (400 MHz, CDCl3): d 0.45 (s,

776
W. Zhang et al. / Tetrahedron: Asymmetry 17 (2006) 767–777
18H), 4.20 (dd, J 5.5, 10.3 Hz, 2H), 4.54 (dd, J 5.5,
9.2 Hz, 2H), 4.65 (dd, J 9.2, 10.3 Hz, 2H), 7.59–7.64
(m, 6H), 7.74 (dd, J 3.3, 6.3 Hz, 2H), 7.97 (dd, J 3.3,
6.3 Hz, 2H), 8.34 (s, 2H). FABMS (m/z) 567
([MꢀOTf]+).
4.22. 3,30-Bis[(40S)-tert-butyloxazolin-20-yl]-2,20-binaph-
thyl copper(I) iodide complex (aS)-18, M = CuI
identical to that described in Section 4.21 shows only
one set of signals. H NMR (400 MHz, CDCl3): d 1.03
(t, J 7.0 Hz, 6H), 3.02 (dd, J 5.6, 9.9 Hz, 2H), 3.18–
3.26 (m, 6H), 4.50 (m, 2H), 4.57–4.68 (m, 4H), 7.11
(dd, J 3.3, 5.5 Hz, 2H), 7.48 (m, 4H), 7.65 (dd, J 3.3,
5.5 Hz, 2H). FABMS (m/z) ([MꢀOTf]+).
1
4.27. Typical procedure for copper(I)-catalyzed asym-
metric cyclopropanation of styrene
1
The H NMR of the solution prepared by dissolving
ligand 2 and CuI following a procedure identical to that
described in Section 4.21 showed only one set of signals.
1H NMR (400 MHz, CDCl3): d 0.42 (s, 18H), 4.38 (dd,
2H, J 5.1, 9.5 Hz), 4.46 (dd, 2H, J 5.1, 9.2 Hz), 4.55
(t, 2H, J 9.3 Hz), 7.58–7.61 (m, 4H), 7.63 (s, 2H), 7.74
(t, 2H, J 5.2 Hz), 7.96 (t, 2H, J 5.2 Hz), 8.36 (s, 2H).
FABMS (m/z) 567 ([MꢀI]+).
4.23. 2,20-Bis[(40S)-(dimethylmethoxymethyl)oxazolin-20-
yl]-1,10-biphenyl copper(I) triflate complex (aR)-19,
R = Me, R0 = Me, M = CuOTf
To a copper(I) triflate benzene complex [Cu(I)OTf-
(C6H6)0.5] (3.3 mg, 13 lmol) was added a solution of
ligand 2 (8.7 mg, 17 lmol) in dichloromethane (1.0 mL)
and then the suspension stirred at room temperature
for 2 h under an argon atmosphere. The resulting solu-
tion was filtered through a membrane filter. After the
addition of styrene (104 mg, 1.0 mmol), a solution of
L-menthyl diazoacetate (290 mg, 1.3 mmol) in dichloro-
methane (1.0 mL) was slowly added over a period of 4 h
and then the reaction solution was stirred at room tem-
perature for an additional 24 h. The reaction mixture
was filtered through an alumina short column and the
filtrate was concentrated under reduced pressure to give
an oil product. The ratio of the trans- and cis-products
of the oil and the diastereomeric excess of them were
determined by GC with DB-1. The absolute configura-
tion of the trans- and cis-products was determined by
comparison of the specific rotation of their correspond-
ing ethyl ester after transesterification in the presence of
a sulfuric acid catalyst with the reported one.13
1
The H NMR of the solution prepared by dissolving
ligand 6b and [Cu(I)OTf(C6H6)0.5] following a proce-
dure identical to that described in Section 4.21 shows
1
only one set of signals. H NMR (400 MHz, CDCl3):
d 0.67 (s, 6H), 1.01 (s, 6H), 2.99 (s, 6H), 4.33 (dd, J
5.5, 10.3 Hz, 2H), 4.56 (dd, J 8.8, 10.3 Hz, 2H), 4.77
(dd, J 5.5, 8.8 Hz, 2H), 7.09 (m, 2H), 7.43–7.49 (m,
4H), 7.70 (m, 2H). FABMS (m/z) 499 ([MꢀOTf]+).
4.24. 2,20-Bis[(40S)-[dimethylmethoxymethyl]oxazolin-20-
yl]-1,10-biphenyl copper(I) iodide complex (aR)-19,
R = Me, R0 = Me, M = CuI
Acknowledgements
1
This work was partly supported by the Excellent Young
Teachers Program of MOE, PR China and the National
Natural Science Foundation of China (No. 20572070).
The H NMR of the solution prepared by dissolving
ligand 6b and CuI following a procedure identical to
that described in Section 4.21 shows only one set of sig-
1
nals. H NMR (400 MHz, CDCl3): d 0.63 (s, 6H), 1.01
(s, 6H), 3.00 (s, 6H), 4.44–4.51 (m, 4H), 4.70 (dd, J
1.9, 5.2 Hz, 2H), 7.09 (dd, J 1.8, 7.3 Hz, 2H), 7.42 (dt,
J 1.8, 7.3 Hz, 2H), 7.45 (dt, J 1.8, 7.3 Hz, 2H), 7.71
(dd, J 1.8, 7.3 Hz, 2H). FABMS (m/z) 499 ([MꢀI]+).
4.25. 2,20-Bis[(40R)-(methoxymethyl)oxazolin-20-yl]-1,10-
biphenyl copper(I) triflate complex (aR)-19, R = H,
R0 = Me, M = CuOTf
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