Synthesis of novel chiral oxazoline ligands and application in the highly enantioselective diethylzinc addition to N-diphenylphosphinoylimines

Article abstract of DOI:10.1016/j.tetasy.2007.10.035

Two sets of novel chiral oxazoline ligands were designed and conveniently prepared from readily available l-aspartic acid and evaluated in enantioselective diethylzinc addition to N-diphenylphosphinoyl imines. In the presence of stoichiometric amounts of these ligands, high enantioselectivities (up to 95% ee) and yields (up to 85%) were achieved for several aromatic imines in toluene at room temperature. Furthermore, the effect of the structure of the ligand on the reaction was studied.

Full text of DOI:10.1016/j.tetasy.2007.10.035

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2643–2648
Synthesis of novel chiral oxazoline ligands and application
in the highly enantioselective diethylzinc addition to
N-diphenylphosphinoylimines
Gexin Yan,a Yong Wu,a,* Wenqing Linb and Xiaomei Zhangb,*
aKey laboratory of Drug-Targeting of the Education Ministry Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
bKey Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China
Received 3 September 2007; accepted 22 October 2007
Abstract—Two sets of novel chiral oxazoline ligands were designed and conveniently prepared from readily available L-aspartic acid and
evaluated in enantioselective diethylzinc addition to N-diphenylphosphinoyl imines. In the presence of stoichiometric amounts of these
ligands, high enantioselectivities (up to 95% ee) and yields (up to 85%) were achieved for several aromatic imines in toluene at room
temperature. Furthermore, the effect of the structure of the ligand on the reaction was studied.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
and employed in promoting enantioselective diethylzinc
addition to N-diphenylphosphinoylimines.5b,d
Chiral amines are pivotal intermediates for the synthesis of
natural products, physiologically active substances and
pharmaceutical compounds.1 Enantioselective diorgano-
zinc addition to imines is among the most convenient
approaches to the preparation of chiral amines.2 Various
chiral N,O-ligands3 and chiral Lewis acids4 were employed
to promote enantioselective diorganozinc addition to imines.
In the past few years, our group has been engaged in
research regarding enantioselective dialkylzinc addition to
imines.5 Besides derivatives of chiral aminoalcohols, chiral
oxazolines 1–2 (Fig. 1) were firstly developed by our group
Generally, these structurally rigid and conformationally
restricted oxazoline ligands were proved to be efficient
and highly enantioselective in the title reaction. However,
they are still not in competition with chiral amino alcohols
in promoting enantioselective diethylzinc addition to
N-diphenylphosphinoylimines, especially ligand 2, which
exhibited only moderate enantioselectivity as well as poor
reactivity. One of the most important rules in the design
of a chiral ligand is the incorporation of rigidity and flexi-
bility. Therefore, we designed and synthesized two sets of
1a, R1 = Ph
1b, R1 = i-Pr
1f, R2 = 2-Br
1g, R2 = 4-Br
1h, R2 = 2-Me
1c, R1 = Naph
O
O
O
1d, R1 = Bn
1i, R2 = 3-Me
1j, R2 = 4-Me
1k, R2 = 4-MeO
1e, R1 = CH2Naph
N
R1
N
HO
N
Ph
HO
HO
R2
2
1
1
Figure 1. Oxazoline ligands 1 and 2 developed by our group previously.
*
Corresponding authors. Tel./fax: +86 28 85503666 (Y.W.); tel.: +86 28 85257883; fax: +86 28 85229250 (X.Z.); e-mail addresses:
pro_wuy_2002@sohu.com; xmzhang@cioc.ac.cn
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.035

2644
G. Yan et al. / Tetrahedron: Asymmetry 18 (2007) 2643–2648
Ar
Ar
3a, 4a, Ar = Ph
OH
N
OH
N
3b, 4b, Ar =
3c, 4c, Ar =
3d, 4d, Ar =
3e, 4e, Ar =
p
-F-C6H4
-Cl-C6H4
-Br-C6H4
-Naph
O
O
p
p
α
3
4
Figure 2. Oxazoline ligands 3 and 4 synthesized and evaluated in the present study.
novel chiral oxazoline ligands 3 and their diastereomers 4
(Fig. 2). Compared with chiral oxazolines 1–2, 3–4 retain
the rigid oxazoline ring but are more flexible around the
hydroxyl moiety. We suggest that these novel chiral oxaz-
oline ligands might provide better results in activating
enantioselective diethylzinc addition to imines.
2. Results and discussion
Figure 3. X-ray crystal structure of 3a.
As depicted in Scheme 1, L-aspartic acid 5 was treated with
phosphorus trichloride to give anhydride 6. Friedel–Crafts
acylation of benzene with anhydride 6 provided amino acid
hydrochloride 7.6 Reduction of both the carbonyl group
and the carboxylic group of 7 with sodium borohydride
and iodine generated a mixture of two diastereomers of
amino diol 8. Acylation of the amino group of 8 facilitated
a mixture of two diastereomers of amide 9. Tosylation of
the primary hydroxyl group of 9 and subsequent in situ
cyclization accomplished the formation of oxazolines 3
and 4. The configuration of 3a was determined by X-ray
analysis of its crystal structure (Fig. 3). Herein, we report
the application of chiral oxazolines 3 and 4 in catalyzing
the addition of diethylzinc to N-diphenylphosphinoyl-
imines which gave interesting results compared with chiral
oxazolines 1–2.
Table 1. Most of the ligands exhibited good reactivities
and high enantioselectivities for the title reaction. Ligands
3e and 4e gave slightly lower yields and enantioselectivities
(Table 1, entries 9 and 10) perhaps due to the bulkier sub-
stituent on 20 carbon of the oxazoline ring. It is noteworthy
that 3b and 4b delivered dramatically low yields as well as
poor enantioselectivities (Table 1, entries 3 and 4). Maybe
this results from the strong electron-withdrawing p-fluoro
substituent on the phenyl group on 20 carbon of the oxazo-
line ring which made it difficult for the ligand to coordinate
with zinc.
It was found that the configuration of the product was
determined by the configuration of the carbon bonded to
the hydroxyl group in the ligand. When the configuration
of this carbon was inverted, but that of the carbon bonded
to nitrogen in the oxazoline ring maintained, the configura-
tion of the product was inverted. According to Table 1,
First, N-diphenylphosphinoyl benzalimine 10a was used as
the standard substrate to check the effect of ligands. The
results of diethylzinc addition to imine 10a in the presence
of stoichiometric amounts of 3 and 4 are summarized in
OH
NH2
O
NH2.HCl
CO2H
O
O
O
NH2
c
a
b
OH
HO
O
OH
O
HCl.H2N
7
8
5
6
Ar
OH
N
N
O
O
3a, 4a, Ar = Ph
d
OH
NH
Ar
e
3b, 4b, Ar =
3c, 4c, Ar =
3d, 4d, Ar =
p
-F-C6H4
-Cl-C6H4
-Br-C6H4
3
p
Ar
p
OH
OH
α
3e, 4e, Ar = -Naph
9
O
4
Scheme 1. Reagents and conditions: (a) PCl3 (1 equiv), THF, rt, quant.; (b) AlCl3 (2.6 equiv), benzene, MeNO2, reflux, 4 M HCl, 0 ꢁC, 65%; (c) NaBH4
(4 equiv), I2 (1.1 equiv), THF, reflux, 76% (two diastereomers); (d) ArCOCl (1 equiv), NaHCO3 (1.5 equiv), THF, rt, 80–90% (two diastereomers); (e) TsCl
(1 equiv), Et3N, CH2Cl2 or THF, reflux, 70–90% (two diastereomers), silica gel chromatography (molar ratio 3:4 ꢀ 5:6).

G. Yan et al. / Tetrahedron: Asymmetry 18 (2007) 2643–2648
2645
Table 1. Enantioselective diethylzinc addition of N-diphenylphosphinoyl
benzalimine 10a in the presence of chiral oxazolines 3 and 4a
location. Whereas (R,S)-2 coordinates with zinc to form
a less stable five-membered ring in which the phenyl group
is situated in an axial location. Hence, (R,S)-3 and (S,S)-1a
delivered higher enantioselectivities than their diastereo-
mers. On the other hand, owing to the flexibility of
(R,S)-3-ZnEt and (S,S)-4-ZnEt, ligand 4 exhibited almost
the same reactivities with ligands 3 and slightly lower
enantioselectivities than ligands 3. However, ligand 2 gave
much lower yield as well as enantioselectivity than ligand
1a due to the rigidity of (S,S)-1a-ZnEt and (R,S)-2-ZnEt.
O
P
O
P
Ph
Ph
Ph
Ph
N
HN
*
Et2Zn, L*
H
Toluene, RT
10a
11a
Entry
Ligands
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
6
7
8
3a
4a
3b
4b
3c
80
89
19
13
86
82
79
78
74
75
77
56
91
85
70
50
89
83
90
86
85
83
91
76
S
R
S
R
S
R
S
R
S
R
S
R
Afterwards, the optimal ligand 3a was applied to promote
diethylzinc addition of various N-diphenylphosphinoyl-
imines (Table 2). As shown in Table 2, most of the sub-
strates underwent the title reaction smoothly to give the
corresponding products in good yields ranging from 76%
to 85% and high enantioselectivities ranging from 86 to
95%. However, imine 10b was almost unreactive. Once
again, the p-fluoro substituent on the phenyl group of the
substrate exhibited a deleterious effect on the reaction.
4c
3d
4d
3e
9
10
11
12
4e
1a5b
25b
a Unless specified otherwise, reactions were carried out in the presence of
stoichiometric amounts of oxazoline and 5.0 equiv of Et2Zn on 0.1 mmol
scale in 2.0 mL of toluene at room temperature for 48 h.
b Isolated yield based on imine.
Table 2. Enantioselective diethylzinc addition of N-diphenylphosphinoyl-
imine 10 in the presence of chiral oxazolines 3aa
Ph
c Determined by HPLC (Chiralcel OD).
OH
N
O
d Determined by comparison of the retention time with the literature
values.6
O
P
O
P
Ph
Ph
Ph
Ph
3a (1 equiv)
N
HN
*
(R,S)-3 resulted in S-11a, (S,S)-4 gave R-11a. Meanwhile,
the configuration of the carbon bonded to nitrogen in the
oxazoline ring affected the enantioselectivities. In general,
(R,S)-3 resulted in higher enantioselectivities than their dia-
stereomers (S,S)-4 (Table 1, entries 1–10). Interestingly, on
the contrary, (S,S)-1a gave much higher yield as well as
enantioselectivity than its diastereomer (R,S)-2 (Table 1,
entries 11 and 12).5b It might be reasoned from the different
catalytic intermediates generated from the different cata-
lytic systems (Fig. 4). (R,S)-3 coordinates with zinc to form
a stable six-membered ring in which both the phenyl group
and the oxazoline ring are situated in an equatorial loca-
tion. Whereas (S,S)-4 coordinates with zinc to form a less
stable five-membered ring in which the phenyl group is
situated in an axial location. (S,S)-1a coordinates with zinc
to form a stable five-membered ring in which both the phen-
yl group and the oxazoline ring are situated in equatorial
Ar
H
Et2Zn, Toluene, RT
Ar
10
11
Ar
Ph
Imine
Yieldb (%)
eec (%)
10a
10b
10c
10d
10e
10f
10g
10h
80
Trace
76
85
78
81
83
84
91
—
88
94
94
95
92
86
p-FC6H4–
p-ClC6H4–
p-BrC6H4–
p-MeOC6H4–
p-BnOC6H4–
Piperonyl
b-Naphthyl
a Unless specified otherwise, reactions were carried out in the presence of
stoichiometric amounts of oxazoline and 5.0 equiv of Et2Zn on 0.1 mmol
scale in 2.0 mL of toluene at room temperature for 48 h.
b Isolated yield based on imine.
c Determined by HPLC (Chiralcel OD or AX).
O
Ar
O
O
Ar
3. Conclusion
N
Ph
(
N
O
In conclusion, two sets of chiral oxazolines were designed
and prepared from L-aspartic acid conveniently. Their
application in promoting diethylzinc addition of various
N-diphenylphosphinoylimines provided corresponding
chiral amines in good yields of 76–85% and high enantio-
selectivities of 88–95%. The configuration of the product
was determined by the configuration of the carbon bonded
to the hydroxyl group in the ligand. Ligands (R,S)-3 resulted
in higher enantioselectivities than ligands (S,S)-4. The fact
was explained by comparing the catalytic intermediate gen-
erated from the (R,S)-3 and diethylzinc with the catalytic
intermediate generated from the (S,S)-4 and diethylzinc.
Zn Et
Zn Et
Ph
R,S)-3-ZnEt
(S,S)-4-ZnEt
Et Zn
O
Et Zn
O
Ph
N
N
Ph
Ph
O
Ph
O
(R,S)-2-ZnEt
(S,S)-1a-ZnEt
Figure 4. Catalytic intermediates generated from (R,S)-3, (S,S)-4, (S,S)-
1a, (R,S)-2 and diethylzinc.

2646
G. Yan et al. / Tetrahedron: Asymmetry 18 (2007) 2643–2648
4. Experimental
4.2.1.3. (S)-3-Amino-1-phenylbutane-1,4-diol 8. Amino
acid hydrochloride 7 (15.0 g, 0.065 mol, 1 equiv) was sus-
pended in dry THF (200 mL). NaBH4 (9.9 g, 0.26 mol,
4 equiv) was added slowly at 0 ꢁC. Afterwards the reaction
mixture was cooled with an ice-salt bath, then I2 (18.1 g,
0.0715 mol, 1.1 equiv) in dry THF (40 mL) was added
dropwise. After refluxing for 10 h at 70 ꢁC, the mixture
was quenched with MeOH (50 mL). The solvent was evap-
orated under reduced pressure and the residue was dis-
solved in H2O (100 mL). The resulting solution was
added NaOH (13.0 g, 0.325 mol, 5 equiv) and stirred for
5 h at 50 ꢁC. The aqueous solution was extracted with
EtOAc and CH2Cl2 (EtOAc/CH2Cl2 = 1:1, 3 · 150 mL).
The combined organic layers were dried over MgSO4, fil-
tered and evaporated in vacuo. Silica gel chromatography
(gradient elution, EtOAc, EtOAc/EtOH = 3:1 to 1:1) affor-
ded amino diols 8 (two diastereomers, 8.25 g, 0.0455 mol,
70%) as a colourless oil.
4.1. General methods
All starting materials were of the highest commercially
available grade and used without further purification. All
solvents were purified and dried according to standard
methods prior to use. THF (Na, benzophenone), toluene
(Na, benzophenone), CH2Cl2 (CaH2) were distilled under
argon from the drying agents indicated prior to use. Reac-
tions were monitored by thin layer chromatography using
Silica Gel HSGF254 plates. Melting points were measured
on an electrothermal digital melting point apparatus. Opti-
cal rotations were measured on a Perkin–Elmer 341 Polar-
imeter at k = 589 nm (cg/100 mL). IR spectra were
measured with a NICOLET MX-1E FT-IR spectrometer.
1H and 13C NMR (300 MHz and 75 MHz, respectively)
1
spectra were recorded in CDCl3. H NMR chemical shifts
are reported in ppm (d) relative to tetramethylsilane (TMS)
with the solvent resonance employed as the internal stan-
dard (CDCl3, d = 7.26 ppm). Data are reported as follows:
chemical shift, multiplicity (s = singlet, br s = broad sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constants (Hz) and integration. 13C NMR chem-
ical shifts are reported in ppm from tetramethylsilane
(TMS) with the solvent resonance as the internal standard
(CDCl3, d = 77.0 ppm). HRMS-ESI spectra were recorded
on BioTOF Q. HPLC analysis was performed on Waters-
Breeze (2487 Dual k Absorbance Detector and 1525 Binary
HPLC Pump). Chiralpak OD, AS columns were purchased
from Daicel Chemical Industries (Hong Kong, China). All
enantiomer-ratios have been controlled by co-injections of
the pure sample with the racemic substrates. All imines
were prepared according to the general procedure7 and
4.2.1.4. Amides 9. The above amino diols 8 (two dia-
stereomers, 8.25 g, 0.0455 mol, 1 equiv) and NaHCO3
(5.7 g, 0.068 mol, 1.5 equiv) was dissolved or suspended
in dry THF (100 mL). The resulting solution was added
the corresponding acid chloride ArCOCl (0.0455 mol,
1 equiv) at 0 ꢁC, after which warmed to ambient tempera-
ture and stirred for 5 h. The solvent was evaporated under
reduced pressure and the residue was dissolved in H2O
(50 mL). The aqueous solution was extracted with CH2Cl2
(3 · 60 mL). The combined organic layer was washed with
brine, dried over MgSO4, filtered and evaporated in vacuo.
Column chromatography on silica gel (petroleum ether/
EtOAc = 1:1) afforded amides 9 (two diastereomers, 80–
90%) as a foam solid.
1
their H NMR data matched the literature data.
4.2.1.5. Oxazolines 3 and 4. To a stirred solution of the
amides 9 (two diastereomers, 1 equiv) in dry CH2Cl2
(100 mL) and dry Et3N (40 mL) was added TsCl (1 equiv).
The reaction mixture was stirred for 3 h at 0 ꢁC, then
heated up to 60 ꢁC and kept refluxing for 5 h. The solvent
was evaporated under reduced pressure and flash chroma-
tography on silica gel (petroleum ether/EtOAc = 4:1) affor-
ded oxazolines 3 and 4 (two diastereomers, 70–90%) as a
white needle-like crystal. Further purification by column
chromatography on silica gel (CH2Cl2) giving the pure
oxazolines 3 and 4 (molar ratio 3:4 = ca. 5:6), respectively.
4.2. Synthesis of oxazolines 3a–3e and 4a–4e
4.2.1. General procedure. Compounds 6 and 7 were synthe-
sized according to the literature6
4.2.1.1. (S)-3-Amino-dihydrofuran-2,5-dione hydrochlo-
ride 6. To a suspension of L-aspartic acid 5 (13.3 g,
0.1 mol, 1 equiv) in THF (60 mL) (0 ꢁC) was added PCl3
(8.3 mL, 0.1 mol, 1 equiv) dropwise. The mixture was
warmed up to room temperature and stirred for additional
6 h. The resulting solid was filtered, washed with THF and
dried in vacuo to afford the L-aspartic anhydride hydro-
chloride 6 (15.2 g, 0.1 mol, quant.) as white crystals.
4.2.2.
(R)-1-Phenyl-2-((S)-2-phenyl-4,5-dihydrooxazol-4-
20
yl)ethanol 3a. Mp 101–103 ꢁC; ½aꢁD ¼ þ79:3 (c 0.3,
CH2Cl2); IR (Nicolet, cmꢂ1) 3337, 3204, 1638, 1494,
1448, 1363, 1101, 1063, 950, 758, 689, 565; 1H NMR
(300 MHz, CDCl3) d (ppm) 7.98–7.95 (m, 2H), 7.52–7.29
(m, 8H), 5.32 (s, 1H), 5.12 (dd, J = 10.0 Hz, 2.3 Hz, 1H),
4.65–4.60 (m, 1H), 4.60–4.53 (m, 1H), 4.04–3.95 (m, 1H),
2.09–2.03 (m, 1H), 1.99–1.83 (m, 1H); 13C NMR
(75 MHz, CDCl3) d (ppm) 164.0, 144.3, 131.7, 128.4,
128.4, 128.3, 127.3, 127.0, 125.7, 74.2, 73.2, 66.5, 45.9;
HRMS-ESI (m/z): (M+Na+) calcd for C17H17NNaO2,
290.1157; found, 290.1145.
4.2.1.2. (S)-2-Amino-4-oxo-4-phenylbutanoic acid hydro-
chloride 7. Anhydrous AlCl3 (34.7 g, 0.26 mol, 2.6 equiv)
was dissolved in dry MeNO2 (40 mL) and dry benzene
(120 mL) at 0 ꢁC. The above anhydride 6 (15.2 g, 0.1 mol,
1 equiv) was added in portionwise. The resulting brown
suspension was stirred for 30 min at 0 ꢁC. Then the mixture
was refluxed for about 15 h. After cooling to 0 ꢁC, 4 M
aqueous HCl (100 mL) was added to the solution and the
resulting mixture was stirred for 2 h, during which a dark
solid precipitated. After filtration, the residue was purified
by recrystallization from mixture of H2O (20 mL) and ace-
tone (100 mL) to give the desired amino acid hydrochloride
5 (15.0 g, 0.065 mol, 65%) as an off-white solid.
4.2.3. (S)-1-Phenyl-2-((S)-2-phenyl-4,5-dihydrooxazol-4-yl)
20
ethanol 4a. Mp 64–66 ꢁC; ½aꢁD ¼ ꢂ142:0 (c 0.3, CH2Cl2);
IR (Nicolet, cmꢂ1) 3338, 3203, 1638, 1494, 1448, 1363,

G. Yan et al. / Tetrahedron: Asymmetry 18 (2007) 2643–2648
2647
1101, 1063, 950, 758, 689, 565; 1H NMR (300 MHz,
CDCl3) d (ppm) 7.96–7.92 (m, 2H), 7.50–7.29 (m, 8H),
5.15 (dd, J = 10.3 Hz, 5.9 Hz, 1H), 4.77 (d, J = 6.2 Hz,
1H), 4.51 (dd, J = 9.6, 7.7 Hz, 1H), 4.45–4.37 (m, 1H),
4.01 (dd, J = 7.7, 7.7 Hz, 1H), 2.17–2.05 (m, 2H); 13C
NMR (75 MHz, CDCl3) d (ppm) 164.0, 144.5, 131.6,
128.4, 128.3, 127.1, 125.7, 125.6, 73.0, 72.2, 63.1, 44.1;
HRMS-ESI (m/z): (M+Na+) calcd for C17H17NNaO2,
290.1157; found, 290.1140.
4.2.8. (R)-2-((S)-2-(4-Bromophenyl)-4,5-dihydrooxazol-4-
20
yl)-1-phenylethanol 3d. Mp 132–134 ꢁC; ½aꢁD ¼ þ67:0 (c
0.3, CH2Cl2); IR (Nicolet, cmꢂ1) 3374, 3252, 1644, 1590,
1485, 1355, 1271, 1079, 1055, 1010, 834, 750, 700, 561;
1H NMR (300 MHz, CDCl3) d (ppm) 7.83–7.81 (m, 2H),
7.58–7.55 (m, 2H), 7.43–7.29 (m, 5H), 5.11 (dd,
J = 10.4 Hz, 2.4 Hz, 1H), 5.08 (s, 1H), 4.65–4.51 (m, 2H),
4.00 (dd, J = 7.5 Hz, 7.5 Hz, 1H), 2.09–2.03 (m, 1H),
1.98–1.86 (m, 1H); 13C NMR (75 MHz, CDCl3) d (ppm)
163.3, 144.1, 131.7, 129.9, 128.4, 127.4, 126.5, 126.0,
125.7, 74.2, 73.4, 66.6, 45.8; HRMS-ESI (m/z): (M+Na+)
calcd for C17H16BrNNaO2, 368.0262; found, 368.0274.
4.2.4.
(R)-2-((S)-2-(4-Fluorophenyl)-4,5-dihydrooxazol-4-
20
yl)-1-phenylethanol 3b. Mp 92–94 ꢁC; ½aꢁD ¼ þ75:3 (c
0.3, CH2Cl2); IR (Nicolet, cmꢂ1) 3377, 3206, 1643, 1601,
1
1508, 1357, 1227, 1153, 1079, 1057, 844, 751, 700, 556; H
4.2.9.
(S)-2-((S)-2-(4-Bromophenyl)-4,5-dihydrooxazol-4-
20
NMR (300 MHz, CDCl3) d (ppm) 7.98–7.94 (m, 2H),
7.43–7.29 (m, 5H), 7.14–7.08 (m, 2H), 5.19 (s, 1H), 5.11
(dd, J = 10.0 Hz, 2.5 Hz, 1H), 4.65–4.54 (m, 2H), 4.01–
3.97 (m, 1H), 2.09–2.02 (m, 1H), 1.97–1.89 (m, 1H); 13C
NMR (75 MHz, CDCl3) d (ppm) 166.6, 163.3, 163.1,
144.2, 130.8, 130.6, 127.6, 127.3, 125.7, 123.3, 123.3, 115.7,
115.4, 74.2, 73.3, 66.5, 45.8; HRMS-ESI (m/z): (M+Na+)
calcd for C17H16FNNaO2, 308.1063; found, 308.1055.
yl)-1-phenylethanol 4d. Mp 135–137 ꢁC; ½aꢁD ¼ ꢂ142:7
(c 0.3, CH2Cl2); IR(Nicolet, cmꢂ1) 3296, 1637, 1592,
1485, 1399, 1366, 1095, 1075, 1011, 833, 728, 694, 564;
1H NMR (300 MHz, CDCl3) d (ppm) 7.82–7.79 (m, 2H),
7.56–7.53 (m, 2H), 7.45–7.25 (m, 5H), 5.11 (dd,
J = 10.2 Hz, 6.0 Hz, 1H), 4.50 (dd, J = 10.4 Hz, 8.2 Hz,
1H), 4.42–4.32 (m, 1H), 4.23 (d, J = 6.2 Hz, 1H), 4.02
(dd, J = 8.1 Hz, 8.1 Hz, 1H), 2.19–2.06 (m, 2H); 13C
NMR (75 MHz, CDCl3) d (ppm) 163.3, 144.4, 131.6,
129.9, 128.4, 127.2, 126.3, 126.2, 125.6, 73.2, 72.1, 63.3,
44.2; HRMS-ESI (m/z): (M+Na+) calcd for C17H16BrN-
NaO2, 368.0262; found, 368.0273.
4.2.5.
(S)-2-((S)-2-(4-Fluorophenyl)-4,5-dihydrooxazol-4-
20
yl)-1-phenylethanol 4b. Mp 84–86 ꢁC; ½aꢁD ¼ ꢂ148:7 (c
0.3, CH2Cl2); IR (Nicolet, cmꢂ1) 3333, 3190, 1642, 1604,
1508, 1365, 1236, 1152, 1073, 1011, 956, 841, 761, 698,
1
561; H NMR (300 MHz, CDCl3) d (ppm) 7.94–7.89 (m,
4.2.10. (R)-2-((S)-2-(Naphthalen-1-yl)-4,5-dihydrooxazol-4-
20
2H), 7.46–7.28 (m, 5H), 7.09–7.03 (m, 2H), 5.12 (dd,
J = 10.5 Hz, 5.8 Hz, 1H), 4.56–4.47 (m, 2H), 4.44–4.37
(m, 1H), 4.01 (dd, J = 7.9 Hz, 7.9 Hz, 1H), 2.12–2.07 (m,
2H); 13C NMR (75 MHz, CDCl3) d (ppm) 166.5, 163.2,
163.1, 144.5, 130.7, 130.6, 128.4, 127.1, 125.6, 123.5,
123.5, 115.6, 115.3, 73.2, 72.1, 63.1, 44.2; HRMS-ESI (m/z):
(M+Na+) calcd for C17H16FNNaO2, 308.1063; found,
308.1043.
yl)-1-phenylethanol 3e. Mp 124–126 ꢁC; ½aꢁD ¼ þ131:7 (c
0.3, CH2Cl2); IR(Nicolet, cmꢂ1) 3383, 1639, 1587, 1510,
1
1340, 1194, 1127, 1053, 996, 806, 777, 699, 560; H NMR
(300 MHz, CDCl3) d (ppm) 9.07–9.04 (m, 1H), 8.14–8.12
(m, 1H), 8.01–7.98 (m, 1H), 7.91–7.88 (m, 1H), 7.63–7.28
(m, 8H), 5.18 (dd, J = 9.4 Hz, 2.9 Hz, 1H), 5.05 (s, 1H),
4.78–4.62 (m, 2H), 4.00 (dd, J = 7.8 Hz, 7.8 Hz, 1H),
2.18–2.11 (m, 1H), 2.07–1.99 (m, 1H); 13C NMR
(75 MHz, CDCl3) d (ppm) 164.1, 144.3, 133.7, 132.4,
131.1, 129.4, 128.5, 128.4, 127.5, 127.4, 126.2, 126.1,
125.7, 124.6, 123.8, 74.1, 72.1, 67.1, 45.9; HRMS-ESI (m/z):
(M+Na+) calcd for C21H19NNaO2, 340.1313; found,
340.1309.
4.2.6. (R)-2-((S)-2-(4-Chlorophenyl)-4,5-dihydrooxazol-4-
20
yl)-1-phenylethanol 3c. Mp 114–116 ꢁC; ½aꢁD ¼ þ82:0 (c
0.3, CH2Cl2); IR (Nicolet, cmꢂ1) 3304, 3242, 1644, 1595,
1489, 1355, 1271, 1090, 1055, 1012, 836, 750, 699, 563;
1H NMR (300 MHz, CDCl3) d (ppm) 7.90–7.87 (m, 2H),
7.43–7.26 (m, 7H), 5.15 (s, 1H), 5.10 (dd, J = 9.9 Hz,
2.4 Hz, 1H), 4.64–4.53 (m, 2H), 3.99 (dd, J = 7.5 Hz,
7.5 Hz 1H), 2.08–2.02 (m, 1H), 1.98–1.87 (m, 1H); 13C
NMR (75 MHz, CDCl3) d (ppm) 163.2, 144.1, 138.0,
129.7, 128.5, 128.3, 127.3, 125.7, 125.5, 74.1, 73.3, 66.5,
45.7; HRMS-ESI (m/z): (M+Na+) calcd for C17H16ClN-
NaO2, 324.0767; found, 324.0760.
4.2.11. (S)-2-((S)-2-(Naphthalen-1-yl)-4,5-dihydrooxazol-4-
20
yl)-1-phenylethanol 4e. Mp 101–102 ꢁC; ½aꢁD ¼ ꢂ82:7 (c
0.3, CH2Cl2); IR (Nicolet, cmꢂ1) 3400, 1637, 1587, 1509,
1
1355, 1193, 1131, 1088, 998, 810, 780, 699, 570; H NMR
(300 MHz, CDCl3) d (ppm) 9.07–9.04 (m, 1H), 8.11–8.08
(m, 1H), 7.99–7.96 (m, 1H), 7.90–7.88 (m, 1H), 7.65–7.29
(m, 8H), 5.21–5.15 (m, 1H), 4.61–4.49 (m, 2H), 4.12–4.05
(m, 1H), 4.01 (d, J = 6.0 Hz, 1H), 2.26–2.18 (m, 2H); 13C
NMR (75 MHz, CDCl3) d (ppm) 163.9, 144.5, 133.6,
132.0, 131.0, 129.1, 128.4, 128.3, 127.3, 127.1, 126.0,
126.0, 125.5, 124.5, 124.2, 72.1, 72.0, 64.0, 44.6; HRMS-
ESI (m/z): (M+Na+) calcd for C21H19NNaO2, 340.1313;
found, 340.1315.
4.2.7.
(S)-2-((S)-2-(4-Chlorophenyl)-4,5-dihydrooxazol-4-
20
yl)-1-phenylethanol 4c. Mp 122–124 ꢁC; ½aꢁD ¼ ꢂ154:0 (c
0.3, CH2Cl2); IR (Nicolet, cmꢂ1) 3424, 3290, 1636, 1596,
1489, 1403, 1365, 1092, 1074, 1013, 953, 833, 730, 693,
1
566; H NMR (300 MHz, CDCl3) d (ppm) 7.86–7.83 (m,
2H), 7.45–7.28 (m, 7H), 5.11 (dd, J = 10.6 Hz, 5.8 Hz,
1H), 4.53–4.35 (m, 3H), 4.01 (dd, J = 7.8 Hz, 7.8 Hz,
1H), 2.11–2.07 (m, 2H); 13C NMR (75 MHz, CDCl3) d
(ppm) 163.2, 144.5, 137.8, 129.7, 128.6, 128.4, 127.2,
125.8, 125.6, 73.2, 72.0, 63.2, 44.3; HRMS-ESI (m/z):
(M+Na+) calcd for C17H16ClNNaO2, 324.0767; found,
324.0756.
4.3. General procedure for the asymmetric diethylzinc
addition to imines
Imine 10a (30.5 mg, 0.1 mmol) and oxazoline 3a (26.7 mg,
0.1 mmol) were dissolved in toluene (2 mL) under argon.
To the mixture was added Et2Zn in hexane (1 M, 0.5 mL,

2648
G. Yan et al. / Tetrahedron: Asymmetry 18 (2007) 2643–2648
Kim, B. S.; Kang, S. W.; Kim, K. H.; Ko, D. H.; Chung, Y.;
Ha, D. C. Bull. Korean Chem. Soc. 2005, 26, 1501–1502; (x) El-
Shehawy, A. A. Tetrahedron: Asymmetry 2006, 17, 2617–2624.
4. (a) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc.
2000, 122, 12055–12056; (b) Nagai, K.; Fujihara, H.; Kuriy-
ama, M.; Yamada, K.; Tomioka, K. Chem. Lett. 2002, 8–9; (c)
Soeta, T.; Nagai, K.; Fujihara, H.; Kuriyama, M.; Tomioka,
K. J. Org. Chem. 2003, 68, 9723–9727; (d) Boezio, A. A.;
Charette, A. B. J. Am. Chem. Soc. 2003, 125, 1692–1693; (e)
0.5 mmol) at rt. After stirring for 48 h, the reaction was
quenched with saturated aqueous ammonium chloride,
and the aqueous layer was extracted with CH2Cl2. The
combined organic layer was washed with brine, and dried
over anhydrous Na2SO4. After evaporation of the solvent,
the residue was purified through column chromatography
on silica gel to give 11a (26.8 mg, 0.08 mmol, 80%) as a
white powder. The enantiomeric excess of the S-isomer
91% (major) was determined by HPLC (Chirapak OD
column, hexane/propan-2-ol = 95:5; flow rate 1 mL/min;
R-isomer, tR 10.87 min and S-isomer, tR 15.21 min).
´
Boezio, A. A.; Pytkowicz, J.; Coˆte, A.; Charette, A. B. J. Am.
´
Chem. Soc. 2003, 125, 14260–14261; (f) Coˆte, A.; Boezio, A.
A.; Charette, A. B. Angew. Chem., Int. Ed. 2004, 43, 6525–
´
6528; (g) Coˆte, A.; Boezio, A. A.; Charette, A. B. Proc. Natl
´
Acad. Sci. 2004, 101, 5405–5410; (h) Desrosiers, J. N.; Coˆte,
A.; Charette, A. B. Tetrahedron 2005, 61, 6186–6192; (i) Shi,
M.; Wang, C. J. Adv. Synth. Catal. 2003, 345, 971–973; (j) Shi,
M.; Zhang, W. Tetrahedron: Asymmetry 2003, 14, 3407–3414;
(k) Wang, C. J.; Shi, M. J. Org. Chem. 2003, 68, 6229–6237; (l)
Shi, M.; Lei, Z. Y.; Xu, Q. Adv. Synth. Catal. 2006, 348, 2237–
2242; (m) Zhang, W.; Shi, M. Synlett 2007, 19–30; (n) Porter,
J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 984–985; (o) Porter, J. R.; Traverse, J.
F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001,
123, 10409–10410; (p) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. Abstr. Paper Am. Chem. Soc. 2001, 221,
U140; (q) Traverse, J. F.; Porter, J. R.; Akullian, L. C.;
Hoveyda, A. H.; Snapper, M. L. Abstr. Paper Am. Chem. Soc.
2002, 224, U209; (r) Traverse, J. F.; Hoveyda, A. H.; Snapper,
M. L. Org. Lett. 2003, 5, 3273–3275; (s) Akullian, L. C.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003,
42, 4244–4247; (t) Akullian, L. C.; Porter, J. R.; Traverse, J.
E.; Snapper, M. L.; Hoveyda, A. H. Adv. Synth. Catal. 2005,
347, 417–425; (u) Wang, M. C.; Liu, L. T.; Hua, Y. Z.; Zhang,
J. S.; Shi, Y. Y.; Wang, D. K. Tetrahedron: Asymmetry 2005,
16, 2531–2534; (v) Wang, M. C.; Xu, C. L.; Zou, Y. X.; Liu, H.
M.; Wang, D. K. Tetrahedron Lett. 2005, 46, 5413–5416; (w)
Wang, M. C.; Xu, C. L.; Cheng, F.; Ding, X. Tetrahedron
2006, 62, 12220–12226; (x) Nishimura, T.; Yasuhara, Y.;
Hayashi, T. Org. Lett. 2006, 8, 979–981; (y) Basra, S.; Fennie,
M. W.; Kozlowski, M. C. Org. Lett. 2006, 8, 2659–2662.
5. (a) Zhang, X. M.; Gong, L. H.; Mi, A. Q.; Cui, X.; Jiang, Y.
H.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron Lett. 2001, 42,
6369–6372; (b) Zhang, X. M.; Lin, W. Q.; Gong, L. Z.; Mi, A.
Q.; Cui, X.; Jiang, Y. Z.; Choi, M. C. K.; Chan, A. S. C.
Tetrahedron Lett. 2002, 43, 1535–1537; (c) Zhang, H. L.;
Zhang, X. M.; Gong, L. Z.; Mi, A. Q.; Cui, X.; Jiang, Y. Z.;
Choi, M. C. K.; Chan, A. S. C. Org. Lett. 2002, 4, 1399–1402;
(d) Zhang, X. M.; Zhang, H. L.; Lin, W. Q.; Gong, L. Z.; Mi,
A. Q.; Cui, X.; Jiang, Y. Z.; Yu, K. B. J. Org. Chem. 2003, 68,
4322–4329; (e) Zhang, H. L.; Fang, C. M.; Li, X.; Gong, L. Z.;
Mi, A. Q.; Cui, X.; Jiang, Y. Z. Chin. J. Chem. 2003, 21, 955–
959; (f) Zhang, H. L.; Jiang, F.; Zhang, X. M.; Cui, X.; Gong,
L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. Chem. Eur. J. 2004,
10, 1481–1492; (g) Liu, H.; Zhang, H. L.; Wang, S. J.; Mi, A.
Q.; Jiang, Y. Z.; Gong, L. Z. Tetrahedron: Asymmetry 2005,
16, 2901–2907; (h) Zhang, H. L.; Liu, H.; Cui, X.; Mi, A. Q.;
Jiang, Y. Z.; Gong, L. Z. Synlett 2005, 615–618; (i) Yang, W.
W.; Cun, L. F.; Zhi, Y. G.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z.
Lett. Org. Chem. 2005, 2, 605–607; (j) Zhang, H. L.; Zhang, X.
M.; Li, X.; Mi, A. Q.; Cui, X.; Jiang, Y. Z. Chin. Chem. Lett.
2005, 16, 1147–1150; (k) Li, X.; Cun, L. F.; Gong, L. Z.; Mi,
A. Q.; Jiang, Y. Z. Tetrahedron: Asymmetry 2003, 14, 3819–
3821.
Acknowledgements
We are grateful for financial support from the National
Natural Science Foundation of China (Project 20572109)
and Sichuan Youth Science and Technology Foundation.
References
1. (a) Blaser, H. U.; Spindler, F. In Comprehensive Asymmetric
Catalysis; Springer: Berlin, 1999; Vol. 1, p 247; (b) Ohkuma,
T.; Noyori, R. In Comprehensive Asymmetric Catalysis;
Springer: New York, 2004; p 43.
2. For reviews, see: (a) Soai, K. J. Syn. Org. Chem. Jpn. 2004, 62,
673–681; (b) Wang, M. C.; Wang, D. K. Prog. Chem. 2004, 16,
918–925; (c) Weinreb, S. M.; Orr, R. K. Synthesis-Stuttgart
2005, 1205–1227; (d) Charette, A. B.; Boezio, A. A.; Cote, A.;
Moreau, E.; Pytkowicz, J.; Desrosiers, J. N.; Legault, C. Pure
Appl. Chem. 2005, 77, 1259–1267.
3. (a) Katritzky, A. R.; Harris, P. A. Tetrahedron: Asymmetry
1992, 3, 437–442; (b) Soai, K.; Hatanaka, T.; Miyazawa, T.
J. Chem. Soc., Chem. Commun. 1992, 1097–1098; (c) Hayase,
T.; Inoue, Y.; Shibata, T.; Soai, K. Tetrahedron: Asymmetry
1996, 7, 2509–2510; (d) Suzuki, T.; Narisada, N.; Shibata, T.;
Soai, K. Tetrahedron: Asymmetry 1996, 7, 2519–2522; (e)
Suzuki, T.; Shibata, T.; Soai, K. J. Chem. Soc., Perkin Trans. 1
1997, 2757–2760; (f) Suzuki, T.; Hirokawa, Y.; Ohtake, K.;
Shibata, T.; Soai, K. Tetrahedron: Asymmetry 1997, 8, 4033–
4040; (g) Sato, I.; Kodaka, R.; Shibata, T.; Hirokawa, Y.;
Shirai, N.; Ohtake, K.; Soai, K. Tetrahedron: Asymmetry 2000,
11, 2271–2275; (h) Sato, I.; Kodaka, R.; Soai, K. J. Chem.
Soc., Perkin Trans. 1 2001, 2912–2914; (i) Sato, I.; Hosoi, K.;
Kodaka, R.; Soai, K. Eur. J. Org. Chem. 2002, 3115–3118; (j)
Andersson, P. G.; Guijarro, D.; Tanner, D. Synlett 1996, 727–
728; (k) Andersson, P. G.; Guijarro, D.; Tanner, D. J. Org.
Chem. 1997, 62, 7364–7375; (l) Guijarro, D.; Pinho, P.;
Andersson, P. G. J. Org. Chem. 1998, 63, 2530–2535; (m)
Brandt, P.; Hedberg, C.; Lawonn, K.; Pinho, P.; Andersson, P.
G. Chem. Eur. J. 1999, 5, 1692–1699; (n) Brandt, P.;
Andersson, P. G. Synlett 2000, 1092–1106; (o) Pinho, P.;
Andersson, P. G. Tetrahedron 2001, 57, 1615–1618; (p)
`
Jimeno, C.; Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.;
Riera, A. Tetrahedron Lett. 1999, 40, 777–780; (q) Jimeno, C.;
Reddy, K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A.
Org. Lett. 2000, 2, 3157–3159; (r) Dahmen, S.; Bra¨se, S. J. Am.
Chem. Soc. 2002, 124, 5940–5941; (s) Hermanns, N.; Dahmen,
S.; Bolm, C.; Bra¨se, S. Angew. Chem., Int. Ed. 2002, 41, 3692–
3694, 3522; (t) Bra¨se, S.; Dahmen, S.; Hofener, S.; Lauterwas-
ser, F.; Kreis, M.; Ziegert, R. E. Synlett 2004, 2647–2669; (u)
Beresford, K. J. M. Tetrahedron Lett. 2002, 43, 7175–7177; (v)
Beresford, K. J. M. Tetrahedron Lett. 2004, 45, 6041–6044; (w)
`
6. Lin, W. Q.; He, Z.; Zhang, H. L.; Zhang, X. M.; Mi, A. Q.;
Jiang, Y. Z. Synthesis 2001, 7, 1007.
7. Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561.