Asymmetric synthesis of chiral oxazolines by organocatalytic cyclization of α-aryl isocyanoesters with aldehydes

Article abstract of DOI:10.1055/s-0029-1217549

A cinchona alkaloid derivative catalyzed the asymmetric formal [3+2] cycloaddition of α-aryl isocyanoesters with aldehydes, affording highly substituted 2-oxazolines with good stereoselectivities of up to 18:1 dr and 90% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217549

LETTER
2191
Asymmetric Synthesis of Chiral Oxazolines by Organocatalytic Cyclization of
a-Aryl Isocyanoesters with Aldehydes
A
symmetric Synthesis
e
of Chiral
O
n
xazolines g-Xia Xue,a,c Chang Guo,b Liu-Zhu Gong*a,b
a
Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, P. R. of China
b
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei 230026, P. R. of China
Fax +86(551)3606266; E-mail: gonglz@ustc.edu.cn
c
Graduate School of Chinese Academy of Sciences, Beijing 100049, P. R. of China
Received 9 April 2009
In view of the reactivity of intermediates of type I, we en-
visioned that if it was possible to initiate an aldol reaction
of the isocyanoesters 1 with aldehydes under the catalysis
of alkaloid derivatives, this could allow a straightforward
catalytic approach to optically active oxazolines
(Scheme 1).
Abstract: A cinchona alkaloid derivative catalyzed the asymmetric
formal [3+2] cycloaddition of a-aryl isocyanoesters with aldehydes,
affording highly substituted 2-oxazolines with good stereoselectiv-
ities of up to 18:1 dr and 90% ee.
Key words: cinchona alkaloid, formal [3+2] cycloaddition, a-aryl
isocyanoester, aldehydes, chiral oxazolines
NC
*B
B*
C
H
For a long time, chiral oxazoline derivatives have re-
ceived much attention not only because they could be
used as ligands for metal-catalyzed reactions,1 but also be-
cause they are core components present in some biologi-
cally active natural products.2 Under acid conditions,
oxazolines can be readily transformed into b-hydroxy-a-
amino acids, which are important constituents of peptides
and related compounds,3 as well as other complex natural
products.4 The aldol-type condensation of aldehydes with
isocyanides containing an a-acidic carbon is an important
method for accessing useful 4,5-disubstituted 2-oxazoline
compounds. Since the first asymmetric aldol reaction us-
ing a chiral Au(I) catalyst was reported in 1986 by Ito and
Hayashi,5a the catalytic ability of several chiral transition-
metal complexes, including Au(I),6 Ag(I),7 Pd(II),8 and Pt
(II)8a,b,9 complexes, have been evaluated. Most of the stud-
ies have focused on using a-isocyanoesters bearing an a-
alkyl substituent as the reactants.5b,c However, there are no
reports describing asymmetric organocatalytic variants,
even those involving a-substituted isocyanoesters as sub-
strates. Herein, we report an organocatalytic, enantio-
selective formal [3+2] cycloaddition of a-aryl
isocyanoesters with aldehydes. The approach exploits cin-
chona alkaloid derived compounds as chiral catalysts.
N
Ar
CO2R1
R1O2C
1
Ar
I
R2
O
O
*
2
N
R2
*
CO2R1
Ar
3
Scheme 1 General strategy for organobase-catalyzed formal cy-
cloaddition of a-aryl isocyanoesters with aldehydes
At the outset of the study, we examined the cycloaddition
of methyl a-phenylisocyano acetate (1a) to p-nitrobenzal-
dehyde (2a) in dichloromethane at room temperature in
the presence of 10 mol% of naturally available quinine
(Figure 1). The reaction took place smoothly, but only
36% yield of the desired product 3a was isolated in mod-
erate diastereoselectivity and low enantioselectivity
(Table 1, entry 1). The reaction temperature had little ef-
fect on the enantioselectivity since almost identical enan-
tiomeric excesses were obtained when the reaction was
conducted at either room temperature or slightly elevated
temperature (entries 4 and 6). However, lower tempera-
ture led to inferior enantioselection (entries 5 and 6). In
contrast, the diastereoselectivity was not affected by the
temperature (entries 4, 5 and 6). Evaluation of the organo-
catalysts derived from cinchona alkaloids (Figure 1) re-
vealed that those bearing a C6¢-hydroxy group showed
superior catalytic activity (entries 1–10). Among those
catalysts, 4g was found to be best, affording 96% yield,
6:1 dr, and 76% ee of the product 3a (entry 9). In addition
to dichloromethane, other solvents were also examined
(entries 11–15). However, the results were found to be un-
satisfactory in all cases except using 1,2-dichloroethane,
Recently, inspired by advances in alkaloid catalysis,10 we
have established a formal [3+2] cycloaddition of a-substi-
tuted isocyanoesters with nitroolefins catalyzed by cin-
chona alkaloids, giving 2,3-dihydropyrroles in high yields
and excellent enantioselectivities.11 In this reaction, the
isocyanoesters 1 were activated by a chiral base to form
transient chiral intermediates I, which were able to attack
electrophiles and undergo formal cycloaddition reactions.
SYNLETT 2009, No. 13, pp 2191–2197
x
x
.x
x
.2
0
0
9
Advanced online publication: 15.07.2009
DOI: 10.1055/s-0029-1217549; Art ID: W05309ST
© Georg Thieme Verlag Stuttgart · New York

2192
M.-X. Xue et al.
LETTER
which gave a slightly higher ee, but with a lower diastereo- centration, led to smooth reactions. Under the improved
selectivity (entry 15). Studies on the effect of additives reaction conditions, the cyclization of 1a with 4-nitrobenz-
suggested that addition of 4 Å molecular sieves (MS) to aldehyde 2a gave good results in terms of both yield and
the reaction provided slightly higher enantio- and diaste- stereoselectivity (Table 2, entry 1) in comparison to those
reoselectivities (entries 16 and 17). More interestingly, obtained in more dilute solution (Table 1, entries 17 and
using 4Å molecular sieves and a catalytic amount of am- 18). Applying the reaction conditions to other aldehydes
monium chloride led to a faster reaction, whilst maintain- was also successful. As shown in Table 2, both electron-
ing the stereoselectivity (entry 18).
poor and neutral aromatic and aliphatic aldehydes could
be tolerated. The highly electron-poor benzaldehydes un-
derwent clean cycloaddition reactions, affording fairly
good enantioselectivities ranging from 70% to 88% ee
(entries 1–9). Halogenated benzaldehydes participated in
the cycloaddition reactions with stereoselectivities vary-
ing from 72% to 85% ee; the results obtained depended to
some extent on the position and number of the substitu-
ents (entries 10–16). After a single recrystallization, 99%
After establishing the optimal conditions, we investigated
the generality of the cyclization of 1a with structurally
different aldehydes. However, initial attempts at extend-
ing the protocol to an electronically neutral aldehyde such
as benzaldehyde failed to give satisfactory results, even
when the reaction was conducted for a prolonged period
of time. We found that tuning the ratio of a-isocyanoesters
to aldehydes from 1.2:1 to 2:1, whilst increasing the con-
Table 1 Optimization of Reaction Conditionsa
NC
Ar
Ph
COOMe
10 mol% catalyst
COOMe
CHO
O2N
+
O
N
conditions
3a Ar = 4-O2NC6H4
1a
2a
Entry
1
Cat.
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Temp (°C)
Time (h)
Yield (%)b
36
drc
ee (%)d
15
4a
4b
4c
4d
4d
4d
4e
4f
r.t.
r.t.
r.t.
r.t.
0
23
23
24
23
30
16
34
24
23
24
21
23
23
22
22
23
21
37
5:1
e
2
32
–
31
3
20
1:1
5:1
5:1
5:1
4:1
4:1
6:1
4:1
4:1
3:1
2:1
3:1
4:1
6:1
6:1
6:1
33
4
96
66
5
94
59
6
35
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
96
65
7
97
47
8
66
71
9
4g
4h
4g
4g
4g
4g
4g
4g
4g
4g
96
76
10
11
12
13
14
15
16
17
18
52
60
92
70
toluene
49
35
m-xylene
PhCN
37
72
48
71
DCE
65
79
DCE
71
80f
79f
79g
CH2Cl2
CH2Cl2
65
91
a Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), catalyst (0.01 mmol), solvent (1.0 mL).
b Isolated yield.
c The dr was determined by 1H NMR.
d The ee was determined by HPLC.
e Product not detected.
f With 4 Å MS (100 mg) as the additive.
g With 4 Å MS (100 mg) and 5 mol% NH4Cl as additive.
Synlett 2009, No. 13, 2191–2197 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Chiral Oxazolines
2193
Table 2 Asymmetric Cyclization of Methyl 2-Isocyano-2-phenyl-
acetate (1a) with Different Aldehydes 2 Catalyzed by 4ga
OMe
R
Ph
COOMe
NC
COOMe
10 mol% 4g
N
N
4 Å MS, r.t.
RCHO
+
Ph
5 mol% NH4Cl,
CH2Cl2
O
N
OH
HO
N
1a
2
3
N
4b cinchonine
4a quinine
Entry 2
R
3
Time Yield drc
ee
(d)
(%)b
94
94
71
92
95
78
62
82
85
87
(%)d
1
2
2a
4-O2NC6H4
4-NCC6H4
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
1
6:1
6:1
8:1
6:1
3:1
4:1
2:1
4:1
5:1
4:1
78
84
83
84
88
78
87
70
76
OH
N
2b
2c
2d
2e
2f
3
OMe
N
OR1
3
3,5-(CF3)2C6H3
3-O2NC6H4
2-O2NC6H4
4-F3CC6H4
2
CF3
CF3
NH
N
4
3
N
4d–g
N
S
H
4d, R1 = Bn
5
3
4c
4e, R1 = MeCO
4f, R1 = PhCO
4g, R1= α-C10H7CO
6
4
7
2g
2h
2i
2-F3CC6H4
7
C
10H7 = naphthyl
OH
8
4-MeO2CC6H4
3-NCC6H4
5
N
9
4
HO
10
2j
2,3-(Cl)2C6H3
3aj
4
84
N
(99)e
4h
11
2k
2,6-(Cl)2C6H3
3ak
6
83
18:1 88
(97)e
Figure 1 Catalysts evaluated in this study
12
13
14
15
16
17
18
19
2l
3,5-(F)2C6H3
3,5-(Br)2C6H3
4-BrC6H4
3al
4
4
6
6
4
6
6
5
75
89
80
61
90
44
18
30
6:1
5:1
4:1
5:1
7:1
2:1
4:1
2:1
79
and 97% ee were obtained for the products 3aj and 3ak,
respectively (entries 10 and 11). Electronically neutral
benzaldehyde, heterocyclic, and aliphatic aldehydes were
less reactive toward the a-isocyanoester. Even when the
reaction time was prolonged, the yields were still low;
however, the reactions led to good enantioselectivities of
up to 89% ee (entries 17–19).
2m
2n
2o
2p
2q
2r
2s
3am
3an
3ao
3ap
3aq
3ar
3as
72
76
77
85
74
70
89
3,4-(F)2C6H3
3,4,5-(F)3C6H2
Ph
Finally, we investigated the scope of the reaction using a-
substituted isocyanoesters with 2e as the reaction partner
(Table 3). It was found that a-aryl isocyanoesters partici-
pated in the cyclization with varying results. High yields
(95%) and enantioselectivities (85–90% ee) were ob-
tained for methyl, ethyl, and benzyl a-phenylisocya-
noesters (1a–c; entries 1–3). Varying the a-aryl
substituent on the isocyanoesters from phenyl to 2-chlo-
2-thiophenyl
PhCH2CH2
a The reaction condition: 1a (0.4 mmol), 2 (0.2 mmol), catalyst 4g (10
mol%), 4 Å MS (100 mg), NH4Cl (5 mol%), CH2Cl2 (1.0 mL).
b Isolated yield.
c The dr was determined by 1H NMR.
rophenyl resulted in a decrease in both the yield and d The ee was determined by HPLC.
e After a single recrystallization.
enantioselectivity (entry 4); however, 3-chloro-benzyliso-
cyanoacetate still provided the expected product 3ee in
87% ee (entry 5). The reaction also proceeded with meth-
yl 2-benzylisocyanoacetate (1f) and with methyl isocy-
anoacetate (1g), but the enantioselectivities obtained were
not synthetically useful (entries 6 and 7).
The recrystallization of 3aj (84% ee; Table 2, entry 10)
from a solvent mixture of ethyl acetate and hexane, gave
a single crystal with >99% ee. The X-ray crystal structure
revealed that a (4S,5R)-configuration existed at the two
stereogenic centers (Figure 2).12 The configuration of the
other cycloaddition products were then assigned by anal-
ogy.
Figure 2 X-ray crystal structure of 3aj
Synlett 2009, No. 13, 2191–2197 © Thieme Stuttgart · New York

2194
M.-X. Xue et al.
LETTER
Table 3 Asymmetric Cyclization of Various Isocyanoesters with
Acknowledgment
2ea
We are grateful for financial support from NSFC (20732006).
R1
COOR2
CHO
10 mol% 4g
Ar
NC
4 Å MS, r.t.
R1
NO2
+
5 mol% NH4Cl,
CH2Cl2
References and Notes
COOR2
O
N
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1
2e
Entry 1
R1
R2
3
Time Yield drc
ee
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(%)b
(%)d
1
2
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4
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6
7
1a
Ph
Ph
Ph
Me
Et
3ae
3be
3ce
3de
3ee
3fe
3
95
3:1
3:1
4:1
5:1
4:1
1:1
88
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Bn
4
95
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3-ClC6H4 Me
5
27
53
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Bn
H
Me
Me
6
31
52
1g
3ge
5
89
13:1 31
a Reaction conditions: 1 (0.4 mmol), 2e (0.2 mmol), catalyst 4g (10
mol%), 4 Å MS (100 mg), NH4Cl (5 mol%), CH2Cl2 (1.0 mL).
b Isolated yield.
c The dr was determined by 1H NMR.
d The ee was determined by HPLC.
b-Hydroxy-a-amino acids have found many applications
as key building blocks in the synthesis of biologically ac-
tive substances.3 Oxazolines can be readily transformed
into b-hydroxy-a-amino acid esters easily by exposure to
acidic hydrolysis conditions.5 For example, treatment of
3aa with concentrated aqueous hydrochloric acid solution
in methanol at room temperature, readily generated the
HCl salt of the b-hydroxy-a-amino acid ester in high yield
(Scheme 2).
Ar
Ph
COOMe
HO
Ar
COOMe
HCl
concd HCl
MeOH, r.t.
O
N
NH2
Ph
4aa 85% yield
3aa
Ar = 4-O2NC6H4
Scheme 2 The hydrolysis of oxazoline
In summary, we have disclosed an organocatalytic asym-
metric formal [3+2] cycloaddition of a-isocyanoesters
with a variety of structurally diverse aldehydes, providing
the products with good stereoselectivities of up to 18:1 dr
and 90% ee by exploiting C6¢-hydroxy cinchona alkaloids
as catalysts.13–37 This method provides an efficient alter-
native to metal-catalyzed reactions for the synthesis of op-
tically active 2-oxazolines, the precursors of b-hydroxy-
a-amino acids.38
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2009, No. 13, 2191–2197 © Thieme Stuttgart · New York

LETTER
Chem. 2006, 118, 961. (e) Wu, F.; Hong, R.; Khan, J.; Liu,
Asymmetric Synthesis of Chiral Oxazolines
2195
calcd for C19H14NO3F6: 418.0878; found: 418.0874. The
enantiomeric excess was 83%, determined by HPLC (Daicel
Chiralpak OD-H; hexane–i-PrOH, 94:6; flow rate: 1.0 mL/
min): tR = 17.179 min, 19.110 min.
X.; Deng, L. Angew. Chem. Int. Ed. 2006, 45, 4301; Angew.
Chem. 2006, 118, 4407. (f) Wang, Y.; Liu, X.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 3928. (g) Bartoli, G.; Bosco,
M.; Carlone, A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.;
Ricci, P.; Sambri, L.; Melchiorre, P. Angew. Chem. Int. Ed.
2006, 45, 4966; Angew. Chem. 2006, 118, 5088. (h) Wang,
B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc.
2007, 129, 768. (i) Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.;
Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129,
6364. For early works on alkaloid derivative catalysis, see:
(j) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc.
2004, 126, 9906. (k) Li, H.; Wang, Y.; Tang, L.; Wu, F.;
Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem.
Int. Ed. 2005, 44, 105; Angew. Chem. 2005, 117, 107.
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Chem. Int. Ed. 2008, 47, 3414; Angew. Chem. 2008, 120,
3462.
(17) Methyl 4-Phenyl-5-(3-nitrophenyl)-2-oxazoline-4-
carboxylate (3ad): Yield: 92%; dr 6:1; [a]D20 82.9 (c 0.684,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.85 (s, 3 H), 6.42
(s, 1 H), 6.89–6.92 (m, 2 H), 7.03–7.05 (m, 3 H), 7.22–7.27
(m, 1 H), 7.34 (s, 1 H), 7.80 (s, 1 H), 7.81 (d, J = 1.8 Hz,
1 H); 13C NMR (CDCl3, 100 MHz): d = 172.41, 155.99,
147.68, 137.75, 135.27, 132.95, 128.76, 128.27, 128.11,
126.18, 122.97, 121.99, 84.98, 83.92, 53.63; IR (KBr): 3074,
956, 2356, 1970, 1889, 1729, 165, 1536, 1493, 1441, 1343,
1253, 1111, 729, 706 cm–1; HRMS: m/z [M + 1+] calcd for
C17H15N2O5: 327.0981; found: 327.0977. The enantiomeric
excess was 84%, determined by HPLC (Daicel Chiralpak
OD-H; hexane–i-PrOH, 98:2; flow rate: 1.0 mL/min):
tR = 5.75 min, 6.96 min.
(12) CCDC 720140.
(18) Methyl 4-Phenyl-5-(2-nitrophenyl)-2-oxazoline-4-
carboxylate (3ae): Yield: 95%; dr 3:1; [a]D20 63.9 (c 0.656,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.87 (s, 3 H),
6.99–7.04 (m, 6 H), 7.19 (s, 1 H), 7.27 (s, 1 H); 13C NMR
(CDCl3, 100 MHz): d = 171.46, 156.07, 135.90, 132.90,
132.37, 128.85, 128.62, 127.76, 127.70, 127.03, 124.31,
84.45, 82.03, 53.61; IR (KBr): 3399, 3342, 2923, 1734,
1677, 1531, 1352, 1239, 1187, 1059, 753 cm–1; HRMS:
m/z [M + Na+] calcd for C17H14N2NaO5: 49.0795; found:
349.0790. The enantiomeric excess was 88%, determined by
HPLC (Daicel Chiralpak OD-H; hexane–i-PrOH, 70:30;
flow rate: 1.0 mL/min): tR = 10.158 min, 17.690 min.
(19) Methyl 4-Phenyl-5-(4-trifluoromethylphenyl)-2-
(13) General procedure for the cycloaddition reaction of
isocyanoester to aldehyde catalyzed by 4g: To a solution
of aldehyde 2 (0.2 mmol), catalyst 4g (0.02 mmol), 4 Å MS
(100 mg) and NH4Cl (0.01 mmol) in CH2Cl2 (1.0 mL), was
added an isocyanoester 1 (0.4 mmol). The reaction mixture
was stirred at r.t. until complete. After removal of the
solvent, the residue was analyzed by 1H NMR to determine
the dr and purified through column chromatography on silica
to yield pure product. For spectroscopic data, see supporting
information.
(14) Methyl 4-Phenyl-5-(4-nitrophenyl)-2-oxazoline-4-
carboxylate (3aa): Yield: 94%; dr 6:1; [a]D20 78.3 (c 0.572,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.83 (s, 3 H), 6.40
(s, 1 H), 6.89–6.91 (m, 2 H), 7.02–7.05 (m, 3 H), 7.18 (d,
20
oxazoline-4-carboxylate (3af): Yield: 78%; dr 4:1; [a]D
64.4 (c 0.348, EtOAc); 1H NMR (CDCl3, 400 MHz): d =
3.82 (s, 3 H), 6.37 (s, 1 H), 6.89–6.91 (m, 2 H), 7.03–7.05
(m, 3 H), 7.09 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H),
7.37 (s, 1 H); 13C NMR (CDCl3, 100 MHz): d = 172.63,
156.06, 139.42, 135.50, 128.87, 128.18, 128.06, 127.97,
127.44, 126.55, 126.26, 124.72, 124.69, 85.58, 83.70, 53.55;
IR (KBr): 3068, 2951, 2923, 2852, 1729, 1687, 1621, 1498,
147, 1318, 1258, 1158, 1116, 1064, 847 cm–1; HRMS:
m/z [M + Na+] calcd for C18H14F3NaO3: 372.0818; found:
372.0817. The enantiomeric excess was 78%, determined by
HPLC (Daicel Chiralpak OD-H; hexane–i-PrOH, 85:15;
flow rate: 1.0 mL/min): tR = 10.996 min, 13.343 min.
(20) Methyl 4-Phenyl-5-(2-trifluoromethylphenyl)-2-
oxazoline-4-carboxylate (3ag): Yield: 62%; dr 2:1
J = 8.7 Hz, 2 H), 7.41 (s, 1 H), 7.90 (d, J = 8.8 Hz, 2 H); 13
NMR (CDCl3, 100 MHz): d = 172.22, 155.84, 147.34,
142.58, 135.03, 128.72, 128.06, 128.01, 127.70, 126.00,
122.75, 84.89, 83.82, 53.43; IR (KBr): 3068, 2960, 2918,
2852, 1734, 1677, 1625, 1602, 1522, 1451, 1343, 1253,
C
1116, 861, 838, 743, 701 cm–1; HRMS: m/z [M + 1+] calcd
for C17H15N2O5: 327.0981; found: 327.0972. The
enantiomeric excess was 78%, determined by HPLC (Daicel
Chiralpak OD-H; hexane–i-PrOH, 70: 30; flow rate: 1.0 mL/
min): tR = 10.955 min, 12.329 min.
(15) Methyl 4-Phenyl-5-(4-cyanophenyl)-2-oxazoline-4-
carboxylate (3ab): Yield: 94%; dr 6:1; [a]D20 93.9 (c 0.506,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.82 (s, 3 H), 6.34
(s, 1 H), 6.87–6.89 (m, 2 H), 7.05–7.06 (m, 3 H), 7.10 (d,
J = 8.2 Hz, 2 H), 7.34 (dd, J1 = 4.8 Hz, J2 = 1.7 Hz, 2 H),
7.38 (s, 1 H); 13C NMR (CDCl3, 100 MHz): d = 172.44,
155.93, 140.74, 135.23, 131.54, 128.80, 128.17, 128.12,
127.65, 127.49, 126.16, 118.44, 111.82, 85.28, 83.89, 53.59;
IR (KBr): 3432, 2951, 2225, 1734, 1625, 1498, 1446, 1253,
1116, 851, 748, 701 cm–1; HRMS: m/z [M + 1+] calcd for
C18H15N2O3: 307.1083; found: 307.1081. The enantiomeric
excess was 84%, determined by HPLC (Daicel Chiralpak
OD-H; hexane–i-PrOH, 70: 30; flow rate: 1.0 mL/min):
tR = 13.452 min, 15.280 min.
unseperatable diastereomeric mixture; 1H NMR (CDCl3, 400
MHz): d = 3.2 (s, 1 H), 3.78 (s, 2 H), 6.24 (s, 0.3 H), 6.76 (d,
J = 7.6 Hz, 0.7 H), 6.97 (s, 0.7 H), 7.02–7.04 (m, 2.3 H),
7.08–7.10 (m, 2.7 H), 7.15 (s, 0.3 H), 7.26–7.40 (m,
3.0 H),7.48 (d, J = 7.3 Hz, 0.7 H), 7.63 (d, J = 7.2 Hz,
0.3 H); 13C NMR (CDCl3, 100 MHz): d = 171.96, 156.07,
155.34, 136.59, 134.79, 132.37, 131.19, 129.78, 129.14,
128.78, 128.58, 128.32, 127.87, 127.58, 127.26, 127.07,
126.16, 125.95, 125.40, 125.18, 125.13, 84.34, 83.75, 81.53,
53.61, 52.28; IR (KBr): 3068, 2956, 2927, 2856, 1739, 1621,
1493, 1455, 1309, 1253, 1163, 1121, 936, 762, 734, 706 cm–
1; HRMS: m/z [M + 1+] calcd for C18H15NO3F3: 350.1004;
found: 350.1008. The enantiomeric excess was 87%,
determined by HPLC (Daicel Chiralpak AD-H; hexane–
i-PrOH, 97:3; flow rate: 1.0 mL/min): tR(major) = 15.238
min, 26.670 min, tR(minor) = 37.920 min, 41.071 min.
(21) Methyl 4-Phenyl-5-(4-methoxycarbonylphenyl)-2-
(16) Methyl 4-Phenyl-5-[3,5-di(trifluoromethyl)phenyl]-2-
20
oxazoline-4-carboxylate (3ac): Yield: 71%; dr 8:1; [a]D
48.3 (c 0.544, EtOAc); 1H NMR (CDCl3, 400 MHz): d =
3.86 (s, 3 H), 6.41 (s, 1 H), 6.83–6.85 (m, 2 H), 7.04–7.06
(m, 3 H), 7.40–7.41 (m, 3 H), 7.55 (s, 1 H); 13C NMR
(CDCl3, 100 MHz): d = 172.33, 155.96, 138.33, 134.99,
131.34, 131.00, 129.14, 128.40, 128.30, 127.15, 125.99,
124.33, 121.80, 121.80, 121.76, 121.72, 84.78, 84.17, 53.71;
IR (KBr): 3059, 2951, 2847, 1734, 1630, 1493, 1385, 1343,
1286, 1173, 1125, 890, 842, 739 cm–1; HRMS: m/z [M + 1+]
20
oxazoline-4-carboxylate (3ah): Yield: 82%; dr 4:1; [a]D
79.0 (c 0.38, EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.83
(s, 3 H), 3.85 (s, 3 H), 6.38 (s, 1 H), 6.91–6.93 (m, 2 H),
7.02–7.07 (m, 5 H), 7.71 (s, 1 H), 7.72 (d, J = 8.2 Hz, 2 H);
Synlett 2009, No. 13, 2191–2197 © Thieme Stuttgart · New York

2196
M.-X. Xue et al.
LETTER
13C NMR (CDCl3, 100 MHz): d = 172.38, 168.21, 156.08,
129.09, 128.06, 127.93, 127.11, 126.34, 85.79, 53.55, 52.15,
29.79; IR (KBr): 2960, 2918, 2852, 1720, 1630, 1493, 1437,
1281, 1106, 1017, 805, 739, 706 cm–1; HRMS: m/z [M + 1+]
calcd for C19H18NO5: 340.1185; found: 340.1183. The
enantiomeric excess was 70%, determined by HPLC (Daicel
Chiralpak OD-H, hexane–i-PrOH, 85:15; flow rate: 1.0 mL/
min): tR = 11.629 min, 13.239 min.
7.08 (m, 3 H), 7.18 (dd, J1 = 6.70 Hz, J2 = 1.8 Hz, 2 H), 7.34
(s, 1 H); 13C NMR (CDCl3, 100 MHz): d = 72.76, 156.09,
135.77, 134.45, 130.98, 128.85, 128.09, 127.91, 126.38,
122.18, 85.78, 53.51; IR (KBr): 3059, 3031, 2923, 2847,
1734, 1630, 1493, 1428, 1262, 1111, 833, 743 cm–1; HRMS:
m/z [M + 1+] calcd for C17H15NO3Br: 360.0235; found:
360.0231. The enantiomeric excess was 76%, determined by
HPLC (Daicel Chiralpak OD-H; hexane–i-PrOH, 80:20;
flow rate: 1.0 mL/min): tR = 9.941 min, 11.893 min.
(27) Methyl 4-Phenyl-5-(3,4-difluorophenyl)-2-oxazoline-4-
carboxylate (3ao): Yield: 61%; dr 5:1; [a]D20 66.5 (c 0.49,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.82 (s, 3 H), 6.27
(s, 1 H), 6.75–6.78 (m, 2 H), 6.91–6.74 (m, 3 H), 7.09–7.10
(m, 3 H), 7.35 (s, 1 H); 13C NMR (CDCl3, 100 MHz): d =
172.62, 155.95, 135.54, 128.15, 128.04, 126.24, 123.38,
123.34, 123.32, 123.28, 116.78, 116.61, 116.27, 116.08,
85.11, 83.47, 53.54; IR (KBr): 3068, 2956, 2847, 2352,
1729, 1625, 1517, 1432, 1262, 1111, 876 cm–1; HRMS:
m/z [M + 1+] calcd for C17H14NO3F2: 318.0942; found:
318.0940. The enantiomeric excess was 77%, determined by
HPLC (Daicel Chiralpak OD-H; hexane–i-PrOH, 80:20;
flow rate: 1.0 mL/min): tR = 11.884 min, 13.881 min.
(28) Methyl 4-Phenyl-5-(3,4,5-trifluorophenyl)-2-oxazoline-
4-carboxylate (3ap): Yield: 90%; dr 7:1; [a]D20 87.2 (c
0.912, EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.84 (s,
3 H), 6.21 (s, 1 H), 6.62–6.66 (dd, J1 = 7.9 Hz, J2 = 6.6 Hz,
2 H), 6.91–6.93 (m, 2 H), 7.12–7.14 (m, 3 H), 7.34 (s, 1 H);
13C NMR (CDCl3, 100 MHz): d = 172.56, 155.81, 135.11,
128.33, 126.10, 111.40, 111.34, 111.12, 111.72, 84.64,
53.66, 29.79; IR (KBr): d = 3064, 2956, 2847, 1729, 1696,
1621, 1536, 1488, 1461, 1376, 1253, 1116, 1040, 961, 866
cm–1; HRMS: m/z [M + 1+] calcd for C17H13NO3F3:
(22) Methyl 4-Phenyl-5-(3-cyanophenyl)-2-oxazoline-4-
carboxylate (3ai): Yield: 85%; dr 5:1 [a]D20 36.1 (c 0.488,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.84 (s, 3 H), 6.33
(s, 1 H), 6.88–6.89 (m, 2 H), 7.06–7.08 (m, 3 H), 7.16–7.18
(m, 1 H), 7.20–7.22 (m, 2 H), 7.33 (d, J = 7.1 Hz, 1 H), 7.38
(s, 1 H); 13C NMR (CDCl3, 100 MHz): d = 171.40, 154.89,
136.10, 134.24, 130.57, 130.23, 129.48, 127.70, 127.54,
127.17, 127.05, 125.13, 117.23, 110.99, 84.01, 82.72, 52.55,
28.68; IR (KBr): 3064, 3031, 2951, 2852, 2229, 1734, 1630,
1578, 1493, 1432, 1253, 1111, 805, 753, 691 cm–1; HRMS:
m/z [M + 1+] calcd for C18H15N2O3: 307.1083; found:
307.1085. The enantiomeric excess was 76%, determined by
HPLC (Daicel Chiralpak OD-H; hexane–i-PrOH, 80:20;
flow rate: 1.0 mL/min): tR = 13.320 min, 15.267 min.
(23) Methyl 4-Phenyl-5-(2,6-dichlorophenyl)-2-oxazoline-4-
carboxylate (3ak): Yield: 83%; dr 18:1; [a]D20 13.7 (c 0.3,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.75 (s, 3 H), 6.90
(d, J = 8.0 Hz, 1 H), 6.99 (t, J1 = J2 = 8.0 Hz, 1 H), 7.06–
7.07 (m, 3 H), 7.18 (s, 1 H), 7.23–7.26 (m, 3 H), 7.33 (s,
1 H); 13C NMR (CDCl3, 100 MHz): d = 172.35, 156.10,
136.40, 136.14, 135.29, 131.46, 130.13, 129.94, 128.25,
127.74, 127.38, 126.68, 84.37, 82.56, 53.68, 29.77; IR
(KBr): 3074, 2999, 2947, 2919, 1730, 1617, 1588, 1565,
1489, 1433, 1235, 1126, 772, 740 cm–1; HRMS: m/z calcd
for C17H14NO3Cl2: 349.0272; found: 349.0281. The
336.0848; found: 336.0845. The enantiomeric excess was
85%, determined by HPLC (Daicel Chiralpak OD-H;
hexane–i-PrOH, 80:20; flow rate: 1.0 mL/min): tR = 9.928
min, 11.640 min.
enantiomeric excess was 88%, determined by HPLC (Daicel
Chiralpak AD-H; hexane–i-PrOH, 85:15; flow rate: 1.0 mL/
min): tR = 11.629 min, 13.239 min.
(24) Methyl 4-Phenyl-5-(3,5-difluorophenyl)-2-oxazoline-4-
carboxylate (3al): Yield: 75%; dr 6:1; [a]D20 69.2 (c 0.63,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.83 (s, 3 H), 6.27
(s, 1 H), 6.47–6.55 (m, 3 H), 6.93–6.95 (m, 2 H), 7.09–7.12
(m, 3 H), 7.35 (s, 1 H); 13C NMR (CDCl3, 100 MHz): d =
172.48, 163.80, 163.677, 161.33, 155.88, 139.41, 135.23,
128.14, 126.17, 110.16, 110.09, 109.97, 109.90, 103.63,
103.38, 103.13, 84.97, 83.83, 53.58; IR (KBr): 3068, 2951,
1729, 1625, 1597, 1465, 1258, 1116, 1003, 951, 861, 697
cm–1; HRMS: m/z [M + 1+] calcd for C17H14NO3F2:
(29) Methyl 4,5-Diphenyl-2-oxazoline-4-carboxylate (3aq):
Yield: 44%; dr 2:1; [a]D20 30.7 (c 0.044, EtOAc); 1H NMR
(CDCl3, 400 MHz): d = 3.81 (s, 3 H), 6.35 (s, 1 H), 6.95–
6.6.97 (m, 4 H), 7.02–7.06 (m, 6 H), 7.36 (s, 1 H); 13C NMR
(CDCl3, 100 MHz): d = 156.24, 136.19, 135.36, 128.11,
127.82, 127.57, 127.24, 126.53, 86.44, 53.44, 29.78; IR
(KBr): 3328, 3068, 2956, 1725, 1696, 1621, 1493, 1455,
1258, 1116, 739, 691 cm–1; HRMS: m/z [M + 1+] calcd for
C17H16NO3: 282.1130; found: 282.1137. The enantiomeric
excess was 74%, determined by HPLC (Daicel Chiralpak
OD-H; hexane–i-PrOH, 93:7; flow rate: 1.0 mL/min):
tR = 11.211 min, 13.919 min.
(30) Methyl 4-Phenyl-5-(thiophen-2-yl)-2-oxazoline-4-
carboxylate (3ar): Yield: 18%; dr 4:1; [a]D20 40.4 (c 0.094,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.79 (s, 1 H), 6.66
(s, 1 H), 6.73–6.74 (m, 1 H), 6.84 (m, 1 H), 7.04 (d, J = 1.1
Hz, 1 H), 7.09–7.14 (m, 5 H), 7.29 (s, 1 H); 13C NMR
(CDCl3, 100 MHz): d = 172.37, 155.82, 133.14, 133.04,
131.95, 128.83, 128.70, 128.02, 127.96, 127.48, 126.77,
126.51, 126.11, 83.08, 53.53; IR (KBr): 3059, 2956, 2923,
2861, 1734, 1625, 1488, 1432, 1258, 1116, 691 cm–1;
HRMS: m/z [M + 1+] calcd for C15H14NO3S: 288.0694;
found: 288.0696. The enantiomeric excess was 70%,
determined by HPLC (Daicel Chiralpak OD-H; hexane–i-
PrOH, 98:2; flow rate: 1.0 mL/min): tR = 5.75 min, 6.96 min.
(31) Methyl 4-Phenyl-5-(propylbenzyl)-2-oxazoline-4-
carboxylate (3as): Yield: 30%; dr 2:1; [a]D20 93.9 (c 0.334,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 1.15–1.17 (m,
1 H), 1.40–1.41 (m, 1 H), 2.60–2.69 (m, 2 H), 3.75 (s, 3 H),
5.27 (dd, J1 = 10.4 Hz, J2 = 3.5 Hz, 1 H), 7.02 (d, J = 6.8 Hz,
2 H), 7.03–7.34 (m, 10 H); 13C NMR (CDCl3, 100 MHz):
318.0942; found: 318.0940. The enantiomeric excess was
79%, determined by HPLC (Daicel Chiralpak OD-H;
hexane–i-PrOH, 80:20; flow rate: 1.0 mL/min): tR = 11.150
min, 13.363 min.
(25) Methyl 4-Phenyl-5-(3,5-dibromophenyl)-2-oxazoline-4-
carboxylate (3am): Yield: 89%; dr 5:1; [a]D20 34.9 (c 0.624,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.83 (s, 3 H), 6.22
(s, 1 H), 6.90–6.93 (m, 2 H), 7.03 (d, J = 1.4 Hz, 2 H), 7.11–
7.13 (m, 3 H), 7.33 (d, J = 1.9 Hz, 2 H); 13C NMR (CDCl3,
100 MHz): d = 172.38, 155.88, 139.27, 135.18, 133.51,
128.80, 128.23, 128.13, 126.13, 122.29, 84.63, 83.90, 53.59;
IR (KBr): 3068, 2951, 2842, 1734, 1635, 1588, 1559, 1437,
1253, 1111, 861, 800, 730, 691 cm–1; HRMS: m/z [M + 1+]
calcd for C17H14Br2NO3: 439.9320; found: 439.9315. The
enantiomeric excess was 72%, determined by HPLC (Daicel
Chiralpak OD-H; hexane–i-PrOH, 80:20; flow rate: 1.0 mL/
min): tR = 11.694 min, 13.552 min.
(26) Methyl 4-Phenyl-5-(4-bromophenyl)-2-oxazoline-4-
carboxylate (3an): Yield: 80%; dr 4:1; [a]D20 48.0 (c 0.198,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 3.81 (s, 3 H), 6.29
(s, 1 H), 6.83 (d, J = 6.8 Hz, 2 H), 6.85–6.94 (m, 2 H), 7.06–
Synlett 2009, No. 13, 2191–2197 © Thieme Stuttgart · New York

LETTER
d = 156.04, 140.58, 130.02, 129.72, 129.26, 128.55, 128.48,
Asymmetric Synthesis of Chiral Oxazolines
2197
C17H15ClN2NaO5: 401.0511; found: 401.0499. The
enantiomeric excess of the major product was 53%,
determined by HPLC (Daicel Chiralpak IA-H; hexane–
i-PrOH, 70:30; flow rate: 1.0 mL/min): tR(major) = 7.674
min, 9.116 min, tR(minor) = 11.377 min, 14.367 min.
(35) Methyl 4-(3-Chlorophenyl)-5-(2-nitrophenyl)-2-
128.45, 128.30, 128.06, 127.71, 127.55, 126.56, 126.10,
83.82, 63.72, 53.27, 51.56, 33.83, 32.36, 29.79; IR (KBr):
3064, 3026, 2951, 2852, 1725, 1691, 1621, 1488, 1437,
1370, 1262, 1135, 913, 734, 691 cm–1; HRMS: m/z calcd for
C19H19NO3: 309.1365; found: 309.1367. The enantiomeric
excess of the major product was 89%, determined by HPLC
(Daicel Chiralpak IA-H; hexane–i-PrOH, 90:10; flow rate:
1.0 mL/min): tR = 7.486 min, 8.704 min.
20
oxazoline-4-carboxylate (3ee): Yield: 69%; dr 4:1; [a]D
59.6 (c 0.182, EtOAc); 1H NMR (CDCl3, 400 MHz): d =
3.90 (s, 3 H), 6.91–6.93 (m, 2 H), 6.97 (d, J = 2.1 Hz, 1 H),
7.04 (s, 1 H), 7.05 (s, 1 H), 7.07–7.12 (m, 1 H), 7.26–7.40
(m, 2 H), 7.84 (dd, J1 = 8.2 Hz, J2 = 1.4 Hz, 1 H); 13C NMR
(CDCl3, 100 MHz): d = 170.96, 156.50, 138.12, 133.92,
133.14, 132.06, 129.24, 128.94, 128.50, 127.99, 127.56,
125.43, 124.44, 83.96, 82.30, 53.84, 29.78; IR (KBr): d =
3068, 2927, 2847, 1734, 1625, 1583, 1517, 1446, 1361,
1338, 1253, 1135, 951, 791, 706 cm–1; HRMS: m/z [M + 1+]
calcd for C17H14N2O5Cl: 361.0591; found: 361.0590. The
enantiomeric excess was 87%, determined by HPLC (Daicel
Chiralpak IA-H; hexane–i-PrOH, 80:20; flow rate: 1.0 mL/
min): tR = 8.794 min, 15.807 min.
(32) Ethyl 4-Phenyl-5-(3-nitrophenyl)-2-oxazoline-4-
carboxylate (3be): Yield: 95%; dr 3:1; [a]D20 59.6 (c 0.182,
EtOAc); 1H NMR (CDCl3, 400 MHz): d = 1.28–1.32 (t,
J1 = J2 = 7.0 Hz, 3 H), 4.29–4.42 (m, 2 H), 6.98–7.05 (m,
6 H), 7.19–7.23 (m, 2 H), 7.28–7.32 (t, J1 = J2 = 7.7 Hz,
1 H), 7.39 (s, 1 H), 7.77–7.79 (dd, J1 = 8.2 Hz, J2 = 1.2 Hz,
1 H); 13C NMR (CDCl3, 100 MHz): d = 170.91, 155.97,
147.52, 136.03, 132.89, 132.55, 128.81, 128.65, 127.67,
127.63, 127.12, 124.32, 84.48, 82.08, 62.75, 29.75, 14.07;
IR (KBr): 3437, 3074, 2983, 2946, 2856, 1720, 1625, 1578,
1522, 1446, 1347, 1243, 1116, 946, 876, 795, 734 cm–1;
HRMS: m/z [M + Na+] calcd for C18H16N2NaO5: 363.0951;
found: 363.0953. The enantiomeric excess of major product
was 85%, determined by HPLC (Daicel Chiralpak AD-H;
hexane–i-PrOH, 70:30; flow rate: 1.0 mL/min): tR = 8.755
min, 11.798 min.
(33) Benzyl 4-Phenyl-5-(2-nitrophenyl)-2-oxazoline-4-
carboxylate (3ce): Yield: 95%; dr 4:1 unseperatable
diastereomeric mixture; 1H NMR (CDCl3, 400 MHz): d =
4.66 (d, J = 12.2 Hz, 0.2 H), 4.79 (d, J = 12.1 Hz, 0.2 H),
5.27 (d, J = 12.4 Hz, 0.8 H), 5.38 (d, J = 12.4 Hz, 0.8 H),
6.69 (s, 0.2 H), 6.96–6.99 (m, 5.7 H), 7.18–7.38 (m, 8.7 H),
7.65 (d, J = 8.5 Hz, 0.4 H), 7.76 (d, J = 8.2 Hz, 0.8 H), 7.85
(d, J = 8.2 Hz, 0.2 H); 13C NMR (CDCl3, 100 MHz): d =
170.68, 156.10, 155.00, 147.41, 135.79, 132.92, 129.57,
128.81, 128.74, 128.61, 128.54, 128.47, 128.40, 128.37,
128.24, 128.15, 127.88, 127.67, 27.57, 127.16, 126.34,
124.29, 84.49, 83.04, 82.12, 68.05, 67.23, 29.72; IR (KBr):
3068, 3031, 2918, 2856, 1729, 1630, 1522, 1484, 1451,
1343, 1239, 1116, 955, 857, 729, 701 cm–1; HRMS: m/z
[M + 1+] calcd for C23H19N2O5: 403.1294; found: 403.1290.
The enantiomeric excess of the major product was 90%,
determined by HPLC (Daicel Chiralpak IA-H; hexane–
i-PrOH, 70:30; flow rate: 1.0 mL/min): tR(major) = 9.633
min, 18.810 min, tR(minor) = 13.676 min, 16.793 min.
(34) Methyl 4-(2-Chlorophenyl)-5-(2-nitrophenyl)-2-
oxazoline-4-carboxylate (3de): Yield: 27%; dr 5:1; 1H
NMR (CDCl3, 400 MHz): d = 3.19 (s, 0.5 H), 3.76 (s, 2.5 H),
6.79 (d, J = 1.3 Hz, 0.8 H), 6.97 (d, J = 1.3 Hz, 0.8 H), 7.22–
7.23 (m, 3.4 H), 7.34–7.77 (m, 4.8 H), 8.09 (d, J = 1.3 Hz,
0.2 H); 13C NMR (CDCl3, 100 MHz): d = 170.71, 156.85,
155.27, 135.78, 133.45, 132.11, 131.58, 131.48, 130.86,
129.91, 129.79, 129.52, 129.43, 129.25, 129.13, 127.35,
127.19, 126.77, 125.13, 124.31, 79.40, 78.79, 53.90, 52.52,
29.77; IR (KBr): 3087, 2946, 2856, 1758, 1734, 1621, 1522,
1437, 1347, 1253, 1229, 1121, 1059, 965, 942, 851, 739,
691 cm–1; HRMS: m/z [M + H2O + Na+] calcd for
(36) Methyl 4-Benzyl-5-(2-nitrophenyl)-2-oxazoline-4-
carboxylate (3fe): Yield: 31%; dr 1:1; 1H NMR (CDCl3,
400 MHz): d = 2.53 (d, J = 14.1 Hz, 1 H), 2.91 (d, J = 14.1
Hz, 1 H), 6.52 (s, 1 H), 6.96–6.98 (m, 2 H), 7.08–7.10 (m,
3 H), 7.21 (s, 1 H), 7.25 (s, 1 H), 7.41 (d, J = 1.1 Hz, 1 H),
7.50–7.52 (m, 2 H), 8.07 (d, J = 6.5 Hz, 1 H); 13C NMR
(CDCl3, 100 MHz): d = 172.33, 154.80, 135.76, 133.32,
131.39, 130,37, 129.45, 128.86, 127.79, 126.53, 125.17,
82.25, 0.81, 52.99, 40.23, 29.78; IR (KBr): 3031, 2923,
2856, 1734, 1677, 1630, 1522, 1455, 1347, 1253, 1206,
1106, 1079, 955, 857, 729 cm–1; HRMS: m/z calcd for
C18H16N2O5: 340.1059; found: 340.1066. The enantiomeric
excess was 52%, determined by HPLC (Daicel Chiralpak
AD-H; hexane–i-PrOH, 80:20; flow rate: 1.0 mL/min):
tR(major) = 9.501 min, 11.151 min, tR(minor) = 8.903 min,
10.819 min.
(37) Methyl 5-(2-Nitrophenyl)-2-oxazoline-4-carboxylate
(3ge): Yield: 89%; dr 13:1; 1H NMR (CDCl3, 400 MHz): d
= 3.88 (s, 3 H), 4.54 (dd, J1 = 6.4 Hz, J2 = 2.0 Hz, 1 H), 6.30
(d, J = 6.4 Hz, 1 H), 7.20 (d, J = 2.0 Hz, 1 H), 7.55–7.59 (m,
2 H), 7.70–7.72 (m, 1 H), 8.16 (dd, J1 = 8.2 Hz, J2 = 1.3 Hz,
1 H); 13C NMR (CDCl3, 100 MHz): d = 170.76, 156.35,
146.31, 135.19, 134.51, 134.13, 129.44, 127.74, 126.74,
125.48, 125.05, 79.35, 79.20, 75.96, 71.48, 53.04, 29.71; IR
(KBr): 3078, 3008, 2960, 2866, 1739, 1625, 1573, 1531,
1432, 1347, 1272, 1206, 1173, 1106, 946, 781, 734, 706
cm–1; HRMS: m/z [M + H2O + Na+] calcd for
C11H10N2NaO5: 273.0482; found: 273.0487. The
enantiomeric excess of the major product was 31%,
determined by HPLC (Daicel Chiralpak IA-H; hexane–i-
PrOH, 90:10; flow rate: 1.0 mL/min): tR(major) = 18.105
min, 26.731 min, tR(minor) = 16.855 min, 20.105 min.
(38) The general procedure for hydrolysis of 3: A few drops of
concd HCl were added to a solution of compound 3 in
methanol. The mixture was stirred at room temperature for
30 min, then the solvent was removed to give the product.
Synlett 2009, No. 13, 2191–2197 © Thieme Stuttgart · New York

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