Asymmetric synthesis of O-alkylated tetronic acid derivatives via an organocatalytic Mannich reaction and subsequent intramolecular cyclization

Article abstract of DOI:10.1016/j.tetasy.2011.08.022

The organocatalytic asymmetric Mannich reaction of ethyl 4-chloro-3-oxobutanoate with N-Boc-imines has been studied and Cinchona alkaloids and chiral thiourea-tertiary amines were evaluated as catalysts. A pyrrolidine-based thiourea-tertiary amine was ide

Full text of DOI:10.1016/j.tetasy.2011.08.022

Tetrahedron: Asymmetry 22 (2011) 1536–1541
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of O-alkylated tetronic acid derivatives via an
organocatalytic Mannich reaction and subsequent intramolecular cyclization
⇑
Nian-hua Luo, Xiang Sun, Yun-yun Yan, Shao-zhen Nie, Ming Yan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The organocatalytic asymmetric Mannich reaction of ethyl 4-chloro-3-oxobutanoate with N-Boc-imines
has been studied and Cinchona alkaloids and chiral thiourea-tertiary amines were evaluated as catalysts.
A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst for the transformation.
The Mannich adducts readily underwent a one-pot intramolecular cyclization in the presence of trieth-
ylamine. A number of O-ethyl tetronic acid derivatives were obtained in good yields and enantioselectiv-
ities (up to 91% ee). The products could be further converted to the heteroatomic mimics of
prostaglandins via reaction with primary amines.
Received 15 July 2011
Accepted 24 August 2011
Available online 3 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Jørgensen and co-workers reported the organocatalytic domino
Michael/aldol reaction of 4-chloro-3-oxobutanoate with enals.6
The enantioselective Mannich reaction is a powerful tool for the
preparation of chiral b-amino carbonyl compounds.1 Among the
various carbonyl compounds used in this reaction, 1,3-dicarbonyl
Chiral epoxycyclohexanones were prepared in excellent yields and
enantioselectivities. Córdova and co-workers later found that the
application of 4-bromo-3-oxobutanoate instead of 4-chloro-3-oxo-
butanoate led to a domino Michael/alkylation reaction. Chiral cyclo-
pentanones were thus obtained in good yields and excellent
enantioselectivities.7 Herein, we report the asymmetric organocata-
lytic Mannich reaction of ethyl 4-chloro-3-oxobutanoate with
N-Boc-imines. The consequent intramolecular cyclization provided
O-alkylated tetronic acids in good yields and enantioselectivities.
compounds are especially attractive. Their
a-methylene groups
are acidic enough to allow the generation of enolate anions under
mild reaction conditions. In addition, the chiral multifunctional
amine products are useful intermediates for further elaborations.
Metal-based chiral catalysts have been successfully developed for
this transformation.2 For example, chiral bisoxazoline-copper com-
plexes,2a palladium complexes2b, and lithium binaphtholate salts2c
have been reported to provide good yields and enantioselectivities
for the Mannich reaction of 1,3-dicarbonyl compounds with N-pro-
tectedimines. Over the past decade, asymmetricorganocatalysis has
made great progress.3 Several groups have reported organocatalytic
enantioselective Mannich reactions of 1,3-dicarbonyl compounds
with imines.4 Cinchona alkaloids,4a,b chiral thiourea-tertiary
amines,4c–g chiral Brønsted acids4h,i have been shown to be efficient
catalysts. Ricci and co-workers found that chiral phase transfer cat-
alysts derived from cinchona alkaloids also provided good yields and
enantioselectivities.4j Recently we have developed a number of
2. Results and discussion
Encouraged by Schaus’ work,4a,b we initially evaluated cincho-
nine as the catalyst for the reactions of ethyl 4-chloro-3-oxobut-
anoate
1 and N-protected imines 2a–2b (Scheme 1). The
reactions were carried out in dichloromethane at room tempera-
ture for 48 h. The effect of the protecting groups was found to be
significant. The reaction of 1 with N-Boc-imine 2a afforded b-ami-
no ester 3a in 78% yield. The reaction of N-Ts-imine 2b afforded the
Mannich adduct 3b in only 21% yield. A couple of unidentified side
products were also observed in this case. On the other hand, the
reaction of N-PMP-imine 2c with 1 did not occur at all.
Tetronic acid derivatives are widespread in plant and microbe
metabolites. Many of them possess valuable biological activities.8
The synthesis of chiral tetronic acid derivatives has received con-
siderable attention.9 When compound 3a was treated with trieth-
ylamine, an intramolecular cyclization occurred to give 2-ethyl
tetronic acid derivative 4a in excellent yield.10
organocatalytic reactions with a
-halogenated nucleophiles.5 Chiral
cyclopropanes were obtained in good yields and enantioselectivities
via Michael/intramolecular alkylation pathways. We speculated
that commercially available 4-chloro-3-oxobutanoate would be a
useful nucleophile for asymmetric organocatalytic transformations.
The reactivity of the chloro substituent allows the consequent intra-
molecular substitution to provide chiral cyclic compounds. In 2006,
Compound 4a was obtained in 15% ee as determined by chiral
HPLC analysis. Although 43% ee could be achieved by running the
⇑
Corresponding author. Tel./fax: +86 20 39943049.
E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.022

N. Luo et al. / Tetrahedron: Asymmetry 22 (2011) 1536–1541
1537
O
PG
Ph
O
PG
HN
NHBoc
Ph
Et3N
cinchonine
(10 mol%)
O
O
N
Cl
(400 mol%)
Cl
OEt
Ph
CH2Cl2, rt
CH2Cl2, rt
O
O
OEt
OEt
4a
2a
1
PG=Boc
2b PG=Ts
2c PG=PMP
3a 78%
3b 21%
3c 0%
Scheme 1. Asymmetric Mannich reactions of 4-chloro-3-oxobutanoate 1 with N-protected-imines 2a–2c.
Table 1
Screening of the catalystsa
reaction at ꢀ35 °C, the value was still significantly lower than the
reported data from the cinchonine-catalyzed Mannich reaction of
methyl acetoacetate with N-Boc-imines.4a The 4-chloro substituent
resulted in a loss of enantioselectivity in the reaction. To improve
the enantioselectivity, a series of organocatalysts including cin-
chona alkaloids and chiral thiourea-tertiary amines 5a–5e were
screened. The results are summarized in Table 1. Both cinchonidine
and quinine provided 4a in good yields, but with low enantioselec-
tivities (Table 1, entries 3–4). Quinine derived thiourea 5a also
afforded 4a in low enantioselectivity (Table 1, entry 5).4f,g Takem-
oto’s catalyst 5b provided improved enantioselectivity (Table 1,
entry 6).4e Increasing the steric hindrance of Takemoto’s catalyst
led to catalyst 5c, which provided better enantioselectivity (Table 1,
entry 7).11 However, the more sterically demanding catalysts 5d
and 5e did not further improve the enantioselectivity (Table 1,
entries 8–9).
Boc (1) catalyst
(10 mol%)
O
NHBoc
Ph
O
O
N
+
Cl
CH2Cl2, rt
OEt
Ph
Et3N, rt
O
(2)
OEt
1
2a
4a
CF3
OMe
H
N
S
N
H
N
H
CF3
NH
N
N
S
NH
5b
In order to determine the optimal reaction conditions with cat-
alyst 5c, the effect of the reaction solvent was examined and the
results are summarized in Table 2. Acetonitrile and DMF provided
similar yields and enantioselectivities with dichloromethane
(Table 2, entries 2–3). Methanol afforded a poor yield and enanti-
oselectivity (Table 2, entry 4). Toluene, ether, and THF provided
lower enantioselectivities than dichloromethane (Table 2, entries
5–7). Acetone provided the best results in terms of the enantiose-
lectivity and the yield (Table 2, entry 8). Decreasing the reaction
temperature significantly improved the enantioselectivity (Table 2,
entries 9–11). Good enantioselectivity and yield were achieved at
ꢀ78 °C (Table 2, entry 11). In order to clarify the possible kinetic
resolution effect during the cyclization of 3a to 4a in the presence
of catalyst 5c, product 3a was isolated before the addition of trieth-
ylamine. It was obtained as two inseparable diastereoisomers (82%
yield, dr = 53/47, 83% ee and 81% ee respectively). In addition, only
trace amounts of 4a were observed in the reaction mixture by TLC
analysis. The isolated 3a was then transformed to 4a (84% ee) via
treatment with triethylamine in acetone. These results clearly indi-
cate that catalyst 5c has almost no catalytic activity for the cycliza-
tion of 3a, and the kinetic resolution of 3a did not occur in the
reaction.
5a
F3C
CF3
CF3
CF3
S
S
N
H
N
CF3
N
H
N
H
CF3
H
N
N
5c
5d
CF3
S
N
H
N
H
CF3
N
5e
Entry
Catalyst
Yieldb (%)
eec (%)
The scope of N-Boc-imines was explored and the results are
summarized in Table 3. O-Ethyl tetronic acid derivatives were ob-
tained in good yields, and with moderate to good enantioselectivi-
ties for a number of aryl and heteroaryl N-Boc-imines. The position
of the substituent at the phenyl ring seemed to have a significant
effect on the enantioselectivity. The para-substitution generally re-
sulted in lower enantioselectivity, no matter if an electron-with-
drawing or electron-donating group was introduced (Table 3,
entries 2, 4, 5, 6, 7, 8). ortho-Chloro, and meta-chloro substituted
imines 2b and 2c afforded better enantioselectivities than para-
chloro substituted imine 2d. Similarly, ortho-methoxy substituted
imine 2f gave better enantioselectivity than para-methoxy substi-
tuted imine 2g. 2-Thiophenyl imine 2i provided the product in good
yield and enantioselectivity (Table 3, entry 9), however, 2-furyl
imine 2j gave a lower enantioselectivity (Table 3, entry 10). Cyclo-
hexyl N-Boc-imine 2k provided a lower yield and enantioselectivity
when compared with phenyl N-Boc-imine 2a (Table 3, entry 11).
1
2d
3
4
5
6
7
8
9
Cinchonine
Cinchonine
Cinchonidine
Quinine
5a
5b
5c
5d
5e
78
78
76
74
78
81
83
81
80
15
43
14
17
19
28
45
19
21
a
Reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol) and catalyst
(0.01 mmol) in CH2Cl2 (1 mL) at room temperature for 48 h.
b
Isolated yields.
Determined by HPLC analysis.
The reaction was carried out at ꢀ35 °C.
c
d
A single crystal of product 7b was obtained. Its absolute config-
uration was determined as (R) by X-ray diffraction analysis

1538
N. Luo et al. / Tetrahedron: Asymmetry 22 (2011) 1536–1541
Table 2
Effect of the reaction solventa
Entry
Solvent
T (°C)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
CH2Cl2
Acetonitrile
DMF
Methanol
Toluene
Ether
rt
rt
rt
rt
rt
rt
rt
rt
ꢀ20
ꢀ40
ꢀ78
83
82
80
39
78
75
45
83
83
82
81
45
42
43
5
36
34
11
49
60
73
84
THF
Acetone
Acetone
Acetone
Acetone
9
10
11
a
Reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol) and 5c
(0.01 mmol) in a solvent (1 mL) for 48 h.
Table 3
Synthesis of O-ethyl tetronic acid derivatives from a variety of N-Boc-iminesa
Boc
R
Boc
O
Figure 1. X-ray crystal structure of 7b.
HN
O
O
N
5c
(1)
(10 mol%)
acetone / -78oC
(2) Et3N, rt
Cl
OEt
R
had a detrimental effect on the enantioselectivity. The reaction of
O-ethyl tetronic acid with 2a was also examined, however, no sub-
stantial amount of 4a could be obtained (Scheme 2, eq. 2). The low-
er reactivity of O-ethyl tetronic acid was proposed to account for
these results.
O
OEt
1
4a, 7b-7k
2a, 6b-6k
Entry
R
Yieldb (%)
eec (%)
5c-Catalyzed Mannich reaction of ethyl 4-chloro-3-oxobutano-
ate 1 and N-Boc-imines is suggested to proceed via a bifunctional
catalytic mechanism (Scheme 3).4f The deprotonation of 1 by cata-
lyst 5c gives the enolate anion. In addition to the electrostatic
attraction between the enolate anion and the ammonium cation,
hydrogen bonds are also expected to form. At the same time, N-
Boc-imine 2a is activated through double hydrogen-bonding inter-
actions with the thiourea group of 5c. The consequent nucleophilic
attack and the proton transfer provide product 3a, which is con-
verted in situ to 4a after triethylamine is added.
2-ethoxyl of product 4a could be replaced readily by primary
amines. The treatment of 4a with butyl amine in methanol led to
compound 8 in excellent yield and enantioselectivity (Scheme 4).
The analogs of 8 were previously prepared as the heteroatomic
mimics of prostaglandins, and found to show the pronounced anti-
aggregatory effect.13
1
2
3
4
5
6
7
8
Ph 2a
4a, 80
7b, 82
7c, 70
7d, 80
7e, 80
7f, 85
7g, 88
7h, 81
7i, 78
7j, 75
7k, 65
84
91
89
82
81
83
63
76
86
60
68
2-Cl-C6H4 6b
3-Cl-C6H4 6c
4-Cl-C6H4 6d
4-F-C6H4 6e
2-MeO-C6H4 6f
4-MeO-C6H4 6g
4-CF3-C6H4 6h
2-Thionyl 6i
2-Furyl 6j
9
10
11
cyclohexyl 6k
a
Reactions were carried out with 1 (0.1 mmol), N-Boc-imine (0.1 mmol), 5c
L) was added at
(0.01 mmol) in acetone (1 mL) at ꢀ78 °C for 48 h. Then, Et3N (56
l
room temperature and the reaction was continued for additional 8 h.
b
Isolated yields.
Determined by chiral HPLC analysis.
c
(Fig. 1).12 The absolute configurations of the other products were
assigned analogously.
3. Conclusion
The reaction of ethyl 4-bromo-3-oxobutanoate with 2a was
next studied. Product 4a was obtained in lower yield and enanti-
oselectivity in comparison with ethyl 4-chloro-3-oxobutanoate 1
(Scheme 2, eq. 1). The bigger volume of bromine than chlorine
In conclusion, we have developed an efficient method for the
asymmetric synthesis of O-alkylated tetronic acid derivatives.
Enantioselective Mannich reactions of 4-chloro-3-oxobutanoate
Boc
Boc
O
HN
5c
O
O
N
1.
(10 mol%)
acetone / -78oC
(1) Br
Ph
OEt
Ph
2a
2. Et3N / r.t
O
OEt
4a
69% yield, 61% ee
Boc
O
O
Boc
HN
5c
(10 mol%)
N
acetone / -78oC
(2)
Ph
Ph
O
O
4a
trace
OEt
OEt
2a
Scheme 2. Reaction of ethyl 4-bromo-3-oxobutanoate and O-ethyl tetronic acid with 2a.

N. Luo et al. / Tetrahedron: Asymmetry 22 (2011) 1536–1541
1539
and the residue was purified by flash column chromatography over
silica gel (petroleum ether/ethyl acetate = 2/1) to give product 4a
as a light yellow oil.
N
S
N
CF3
H
H
O
N
t-Bu
Cl
O
4.3. Spectroscopic data of the products
H
O
O
OEt
4.3.1. (S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)
(phenyl) methylcarbamate 4a
CF3
N
Light yellow oil,
½
a 2D0
ꢂ
¼ þ17:4 (c 0.50, CH2Cl2); 1H NMR
Ph
Scheme 3. Proposed transition state.
(400 MHz, CDCl3) d: 7.40 (d, J = 7.2 Hz, 2H), 7.31–7.27 (m, 2H),
7.23–7.19 (m, 1H), 6.56 (d, J = 8.8 Hz, 1H), 5.54 (d, J = 9.2 Hz, 1H),
4.56 (d, J = 16.0 Hz, 1H), 4.51 (d, J = 16.0 Hz, 1H), 4.45 (qd, J = 7.2,
2.0 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.42 (s, 9H); 13C NMR
(100 MHz, CDCl3) d: 194.9, 180.2, 155.2, 142.7, 128.5, 127.1,
126.2, 94.9, 79.3, 74.8, 66.6, 48.4, 28.4, 14.7; IR (thin film)
Boc
Boc
O
O
HN
HN
MeOH
40 oC, 8 h
Ph
Ph
/cmꢀ1: 2978 (m), 2931 (w), 1726 (m), 1618 (m), 1499 (w), 1389
+
m
O
O
NH2
N
OEt
(s), 1015 (m), 757 (w), 700 (m); HRMS (ESI) calcd for C18H23NNaO5
(M+Na)+: 356.1468, found: 356.1470. The enantiomeric excess was
determined by HPLC with a Chiralpak AS–H column (hexane/2-
PrOH = 90/10, k = 254 nm, 1.0 mL/min); tmajor = 19.80 min, tminor
23.28 min, 84% ee.
H
4a
8
95% yield, 87% ee
Scheme 4. Transformation of 4a to compound 8.
=
with a series of N-Boc-imines were achieved in good yields and
enantioselectivities. A pyrrolidine-based chiral thiourea-tertiary
amine was identified as the best catalyst. The consequent intramo-
lecular cyclization of the Mannich adducts in the presence of
triethylamine led to O-alkylated tetronic acid derivatives effi-
ciently. Furthermore, the products could be readily converted to
the heteroatomic mimics of prostaglandins.
4.3.2. (R)-tert-Butyl (2-chlorophenyl) (2-ethoxy-4-oxo-4,5-dihydro
furan-3-yl) methylcarbamate 7b
White solid, mp 125–126 °C; ½a D20
ꢂ
¼ ꢀ13:3 (c 0.48, CH2Cl2); 1H
NMR (400 MHz, CDCl3) d: 7.36 (br, 1H), 7.29–7.19 (m, 3H), 6.57
(d, J = 8.4 Hz, 1H), 5.51 (d, J = 8.8 Hz, 1H), 4.58 (d, J = 16.0 Hz, 1H),
4.53 (d, J = 16.4 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.46–1.42 (m,
12H); 13C NMR (100 MHz, CDCl3) d: 194.7, 180.2, 155.2, 144.7,
134.2, 129.7, 127.3, 126.4, 124.4, 94.3, 79.6, 74.9, 66.8, 48.0, 28.4,
14.7; IR (thin film)
(m), 1496 (w), 1388 (s), 1015 (m), 755(m); HRMS (ESI) calcd for
18H22ClNNaO5 (M+Na)+: 390.1079, found: 390.1077; The enantio-
meric excess was determined by HPLC with a Chiralpak AS–H
m
/cmꢀ1: 2978 (m), 2929 (w), 1728 (m), 1619
4. Experimental
4.1. General
C
1H NMR and 13C NMR spectra were recorded on Bruker AVANCE
400 spectrometer. Chemical shifts of protons are reported in parts
per million downfield from tetramethylsilane (d = 0). Chemical
shifts of carbon are referenced to the central peak of the solvent
(CDCl3, d = 77.0). Peaks are labeled as singlet (s), doublet (d), triplet
(t), quartet (q), and multiplet (m). Optical rotations were measured
on a Perkin–Elmer 341 digital polarimeter. Melting points were
measured on a WRS-2A melting point apparatus and are uncor-
rected. The high resolution mass spectroscopic data were obtained
with Shimadzu LCMS-IT-TOF spectrometer. Infrared (IR) spectra
were recorded on a Bruker Tensor 37 spectrophotometer. Data are
represented as follows: frequency of absorption (cmꢀ1), intensity
of absorption (s = strong, m = medium, w = weak). Enantiomeric ex-
cesses were determined by HPLC using a Daicel Chiralpak AS–H col-
umn (4.6 mm ꢁ 25 cm) and eluting with a hexane/2-PrOH solution.
Flash chromatography was performed over Silica gel (230–
400 mesh), purchased from Qingdao Haiyang Chemical Co., Ltd. Ace-
tone was purchased from Tianjin Fuyu Chemical Co., Ltd and dried
over MgSO4 before use. Commercially available reagents and analyt-
ical grade solvents were used without further purification. N-Boc-
imines were prepared according to the reported procedures.14
column (hexane/2-PrOH = 90/10, k = 254 nm, 1.0 mL/min); tmajor
14.66 min, tminor = 17.57 min, 91% ee.
=
4.3.3. (S)-tert-Butyl (3-chlorophenyl) (2-ethoxy-4-oxo-4,5-
dihydrofuran-3-yl) methylcarbamate 7c
Lightyellowoil, ½a D20
ꢂ
¼ þ23:6 (c0.14, CH2Cl2);1HNMR(400 MHz,
CDCl3) d: 7.36 (br, 1H), 7.29–7.27 (m, 1H), 7.24–7.17 (m, 2H), 6.55 (d,
J = 8.0 Hz,1H),5.51(d,J = 8.4 Hz,1H),4.58(d,J = 16.0 Hz,1H),4.52(d,
J = 16.0 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.42 (s,
9H); 13C NMR (100 MHz, CDCl3) d: 194.7, 180.2, 155.2, 144.8, 134.3,
129.7, 127.3, 126.4, 124.4, 94.3, 79.6, 74.9, 66.8, 48.1, 28.4, 14.7; IR
(thin film)
(w), 1388 (s), 1015 (m), 779(w), 689 (w); HRMS (ESI) calcd for
18H22ClNNaO5 (M+Na)+: 390.1079, found: 390.1079; The enantio-
m
/cmꢀ1: 2979 (m), 2930 (w), 1726 (m), 1617 (m), 1442
C
mericexcesswasdeterminedbyHPLCwithaChiralpakAS–Hcolumn
(hexane/2-PrOH = 90/10, k = 254 nm, 1.0 mL/min); tmajor = 21.55 -
min, tminor =15.76 min, 89% ee.
4.3.4. (S)-tert-Butyl (4-chlorophenyl) (2-ethoxy-4-oxo-4,5-
dihydrofuran-3-yl) methylcarbamate 7d
Light yellow oil,
½
a 2D0
ꢂ
¼ þ29:0 (c 0.10, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d: 7.33(d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H),
6.56 (d, J = 8.4 Hz, 1H), 5.49 (d, J = 8.8 Hz, 1H), 4.57 (d, J = 16.0 Hz,
1H), 4.52 (d, J = 16.0 Hz, 1H), 4.46 (qd, J = 7.2, 1.6 Hz, 2H), 1.45–
1.41 (m, 12H); 13C NMR (100 MHz, CDCl3) d: 194.8, 180.1, 155.2,
141.3, 132.8, 128.6, 127.7, 94.5, 79.6, 74.9, 66.8, 48.0, 28.4, 14.7;
4.2. Typical procedure for asymmetric synthesis of O-ethyl
tetronic acid derivatives
A solution of 5c (4.2 mg, 0.01 mmol) in acetone (0.5 mL) was
stirred at ꢀ78 °C for 10 min. Then, a mixture of 1 (16.4 mg,
0.1 mmol) and 2a (20.5 mg, 0.1 mmol) in acetone (0.5 mL) was
added. The reaction solution was stirred at ꢀ78 °C for 48 h and
IR (thin film)
1489 (w), 1388 (s), 992 (m), 861(m); HRMS (ESI) calcd for
18H22ClNNaO5 (M+Na)+: 390.1079, found: 390.1083; The enantio-
meric excess was determined by HPLC with a Chiralpak AS–H
m
/cmꢀ1: 2979 (m), 2925 (w), 17126 (m), 1590 (m),
C
then warmed to room temperature. After triethylamine (56 lL,
0.4 mmol) was added, the reaction mixture was stirred at room
temperature for 8 h. The solvent was evaporated under vacuum,
column (hexane/2-PrOH = 90/10, k = 254 nm, 1.0 mL/min); tmajor
17.79 min, tminor = 13.99 min, 82% ee.
=

1540
N. Luo et al. / Tetrahedron: Asymmetry 22 (2011) 1536–1541
4.3.5. (S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)
(4-fluorophenyl) methylcarbamate 7e
J = 8.8 Hz, 1H), 4.58 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 1.46–1.42 (m,
12H); 13C NMR (100 MHz, CDCl3) d: 194.7, 180.0, 155.1, 146.4,
126.7, 124.3, 124.0, 94.6, 79.6, 74.9, 66.8, 28.4, 14.7; IR (thin film)
/cmꢀ1: 2978 (m), 2928 (w), 1726 (m), 1581 (m), 1482 (w), 1387 (s),
1012 (m), 763(m), 697(w); HRMS (ESI) calcd for C16H21NNaO5S
(M+Na)+: 362.1033, found: 362.1032; The enantiomeric excess
was determined by HPLC with a Chiralpak AS–H column (hex-
ane/2-PrOH = 90/10, k = 254 nm, 1.0 mL/min); tmajor = 23.06 min,
tminor = 42.31 min, 86% ee.
Light yellow oil,
½
a 2D0
ꢂ
¼ þ58:0 (c 0.10, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d: 7.38–7.35 (m, 2H), 6.99–6.94 (m, 2H), 6.52
(d, J = 8.0 Hz, 1H), 5.51 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 16.4 Hz, 1H),
4.52 (d, J = 16.0 Hz, 1H), 4.46 (qd, J = 7.2, 1.2 Hz, 2H), 1.45–1.41
(m, 12H); 13C NMR (100 MHz, CDCl3) d: 194.8, 180.1, 163.1,
160.7, 155.2, 138.7, 127.9, 127.8, 115.3, 115.1, 94.8, 79.5, 74.8,
66.7, 47.9, 28.4, 14.7; IR (thin film) m
/cmꢀ1: 2979 (m), 2928 (w),
1719 (m), 1618 (m), 1498 (w), 1388 (s), 1054 (m), 838 (w),
700(m); HRMS (ESI) calcd for C18H22FNNaO5 (M+Na)+: 374.1374,
found: .374.1377; The enantiomeric excess was determined by
HPLC with a Chiralpak AS–H column (hexane/2-PrOH = 90/10,
k = 254 nm, 1.0 mL/min); tmajor = 20.56 min, tminor = 18.47 min,
81% ee.
4.3.10. (R)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)
(furan-2-yl) methylcarbamate 7j
Light yellow oil,
½
a 2D0
ꢂ
¼ þ15:0 (c 0.22, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d: 7.31 (br, 1H), 6.28–6.26 (m, 1H), 6.18 (br,
2H), 5.65 (d, J = 9.2 Hz, 1H), 4.58 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H),
1.45–1.42 (m, 12H); 13C NMR (100 MHz, CDCl3) d: 194.8, 180.4,
155.1, 153.9, 141.8, 110.2, 105.7, 92.5, 79.6, 74.9, 66.7, 42.3, 28.4,
4.3.6. (S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)
(2-methoxyphenyl) methylcarbamate 7f
14.7; IR (thin film) m
/cmꢀ1: 2979 (m), 2928 (w), 1727 (m), 1688
White solid, mp 123–124 °C; ½a D20
ꢂ
¼ þ27:5 (c 0.4, CH2Cl2); 1H
(m), 1482 (w), 1389 (s), 1007 (m), 788(m), 734(w); HRMS (ESI)
calcd for C16H21NNaO6 (M+Na)+: 364.1261, found: 364.1267; The
enantiomeric excess was determined by HPLC with a Chiralpak
AS–H column (hexane/2-PrOH = 90/10, k = 254 nm, 1.0 mL/min);
tmajor = 23.39 min, tminor = 33.22 min, 60% ee.
NMR (400 MHz, CDCl3) d: 7.48 (dd, J = 7.6, 1.6 Hz, 1H), 7.20 (td,
J = 8.0, 1.6 Hz, 1H), 6.91 (t, J = 6.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H,),
6.32 (d, J = 9.2 Hz, 1H), 5.88 (d, J = 8.8 Hz, 1H), 4.52–4.40 (m, 4H),
3.82 (s, 3H), 1.45–1.40 (m, 12H); 13C NMR (100 MHz, CDCl3) d:
195.0, 180.1, 156.4, 155.1, 130.1, 128.1, 127.7, 120.4, 110.6, 94.5,
79.1, 74.5, 66.1, 60.3, 55.3, 28.4, 14.7; IR (thin film)
m
/cmꢀ1: 2921
4.3.11. (S)-tert-Butyl cyclohexyl (2-ethoxy-4-oxo-4,5-dihydro-
(m), 2851 (w), 1718 (m), 1591 (m), 1492 (w), 1385 (s), 1051 (m),
752(w), 700(m); HRMS (ESI) calcd for C19H25NNaO6 (M+Na)+:
386.1574, found: 386.1573; The enantiomeric excess was deter-
furan-3-yl) methylcarbamate 7k
Light yellow oil,
½
a 2D0
ꢂ
¼ ꢀ19:2 (c 0.20, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d: 5.89 (d, J = 9.6 Hz, 1H), 4.53–4.42 (m, 4H),
4.22 (t, J = 8.0 Hz, 1H), 1.79–1.60 (m, 6H), 1.44–1.41 (m, 12H),
1.21–1.11 (m, 3H), 0.99–0.86 (m, 2H); 13C NMR (100 MHz, CDCl3)
d: 195.8, 180.8, 155.6, 93.6, 78.8, 74.6, 66.2, 49.6, 43.0, 29.3, 28.4,
26.3, 26.0, 25.9, 14.7; IR (thin film) /cmꢀ1: 2979 (w), 2933 (m),
2922 (w) 1725 (m), 1688 (m), 1451 (w), 1388 (s), 1011 (m), 779
(w); HRMS (ESI) calcd for C18H28NNaO5 (M+Na)+: 362.1938, found:
362.1937; The enantiomeric excess was determined by HPLC with
a Chiralpak AS-H column (hexane/2-PrOH = 90/10, k = 254 nm,
1.0 mL/min); tmajor = 11.16 min, tminor = 16.66 min, 68% ee.
mined by HPLC with
a Chiralpak AS–H column (hexane/
2-PrOH = 90/10, k = 254 nm, 1.0 mL/min); tmajor = 12.18 min, tminor
=
15.88 min, 83% ee.
4.3.7. (S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)
(4-methoxyphenyl) methylcarbamate 7g
Light yellow oil,
½
a 2D0
ꢂ
¼ þ34:9 (c 0.32, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d: 7.33 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz,
2H), 6.49 (d, J = 8.4 Hz, 1H), 5. 49 (d, J = 9.2 Hz, 1H), 4.56 (d,
J = 16.0 Hz, 1H), 4.51 (d, J = 16.0 Hz, 1H), 4.45(qd, J = 7.2, 1.4 Hz,
2H), 3.77 (s, 3H), 1.45–1.41 (m, 12H); 13C NMR (100 MHz, CDCl3)
d: 195.0, 180.1, 158.7, 155.2, 135.1, 127.5, 113.8, 95.1, 79.3, 74.8,
4.4. Preparation of (S)-tert-butyl (2-(butylamino)-4-oxo-4,5-
dihydrofuran-3-yl) (phenyl)methylcarbamate 8
66.6, 55.3, 47.9, 28.4, 14.7; IR (thin film) m
/cmꢀ1: 2978 (m), 2932
(w), 1720 (m), 1617 (m), 1441 (w), 1388 (s), 1013 (m), 860(m);
HRMS (ESI) calcd for C19H25NNaO6 (M+Na)+: 386.1574, found:
386.1572; The enantiomeric excess was determined by HPLC with
a Chiralpak AS–H column (hexane/2-PrOH = 90/10, k = 254 nm,
1.0 mL/min); tmajor = 23.87 min, tminor = 26.18 min, 63% ee.
A solution of 4a (33 mg, 0.1 mmol) and butylamine (0.4 mmol)
in methanol (3 mL) was stirred at 40 °C for 8 h. The solvent was
evaporated under vacuum, and the residue was purified by flash
column chromatography over silica gel (petroleum ether/ethyl ace-
tate = 2/1) to give 8 as a white solid, mp 137–138 °C; ½a D20
¼ þ24:1
ꢂ
(c 0.60, CH2Cl2); 1H NMR (400 MHz, CDCl3) d: 7.30 (br, 2H), 7.22–
7.18 (m, 2H), 7.14–7.11 (m, 1H), 6.67 (s, 1H), 5.47 (d, J = 8.0 Hz,
1H), 4.41 (d, J = 15.2 Hz, 1H), 4.36 (d, J = 15.2 Hz, 1H), 3.16 (br,
2H), 2.13 (s, 1H), 1.33 (s, 9H), 0.81–0.76 (t, J = 7.2 Hz, 3H), 1.19–
1.11 (m, 4H); 13C NMR (100 MHz, CDCl3) d: 191.8, 176.9, 156.4,
141.1, 128.4, 126.9, 126.4, 92.7, 79.5, 74.0, 48.2, 41.1, 31.8, 28.4,
19.7, 13.5; IR (KBr): 3553 (m), 2980 (w), 2873 (m), 1710 (m),
1689 (m), 1671 (m), 1429 (w), 1329 (m), 1076 (m), 811 (w), 752
4.3.8. (S)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)
(4-(trifluoromethyl)phenyl) methylcarbamate 7h
Light yellow oil,
½
a 2D0
ꢂ
¼ þ3:8 (c 0.34, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d: 7.56–7.50 (m, 4H), 6.61 (d, J = 8.4 Hz, 1H),
5.57 (d, J = 8.4 Hz, 1H), 4.61–4.45 (m, 4H), 1.44 (t, J = 6.8 Hz, 3H),
1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) d: 194.7, 180.2, 155.2,
146.7, 129.5, 129.1, 126.5, 125.5, 125.4, 122.8, 94.1, 79.7, 74.9,
66.9, 48.2, 28.4, 14.7; IR (thin film)
1725 (m), 1618 (m), 1484 (w), 1388 (s), 1016 (m), 798(m); HRMS
(ESI) calcd for
19H22F3NNaO5 (M+Na)+: 424.1342, found:
m
/cmꢀ1: 2980 (m), 2930 (w),
(m), 719 (m); HRMS (ESI) calcd for
359.1971, found: 359.1961; The enantiomeric excess was deter-
C
20H27N2O4 (MꢀH)ꢀ:
C
mined by HPLC with a Chiralpak AS–H column (hexane/2-
424.1346; The enantiomeric excess was determined by HPLC with
a Chiralpak AS–H column (hexane/2-PrOH = 90/10, k = 254 nm,
1.0 mL/min); tmajor = 12.86 min, tminor = 9.15 min, 76% ee.
PrOH = 90/10, k = 254 nm, 1.0 mL/min); tmajor = 8.59 min, tminor =
10.93 min, 87% ee.
Acknowledgments
4.3.9. (R)-tert-Butyl (2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)
(thiophen-2-yl) methylcarbamate 7i
Financial support from the National Natural Science Foundation
of China (Nos. 20772160, 20972195), Ministry of Health of China
(No. 2009ZX09501-017), and Fundamental Research Funds for
the Central Universities are gratefully acknowledged.
Light yellow oil,
(400 MHz, CDCl3) d: 7.14 (dd, J = 5.2, 1.2 Hz, 1H), 6.96 (d,
½
a 2D0
ꢂ
¼ þ19:2 (c 0.18, CH2Cl2); 1H NMR
J = 3.2 Hz, 1H), 6.91–6.88 (m, 1H), 6.42 (d, J = 8.8 Hz, 1H), 5.82 (d,

N. Luo et al. / Tetrahedron: Asymmetry 22 (2011) 1536–1541
1541
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Chemical
formula:
C
18H22NO5Cl,
M = 367.82,
orthorhombic,
a = 9.33280(10) Å, b = 10.10570(10) Å, c = 20.4135(2) Å, U = 1925.29(3) Å3,
T = 150.1, space group P212121 (no. 19), Z = 4, _(Cu K)_ = 1.987, 8093
reflections measured, 3541 unique (Rint = 0.0321) which were used in all
calculations. The final wR(F2) was 0.0788 (all data). Absolute structure
parameter Flack = ꢀ0.005(14).
13. (a) Pashkovskii, F. S.; Shchukina, E. M.; Gribovskii, M. G.; Lakhvich, F. A. Russ. J.
Org. Chem. 2008, 44, 657; (b) Pashkovskii, F. S.; Shchukina, E. M.; Gribovskii, M.
G.; Lakhvich, F. A. Russ. J. Org. Chem. 2006, 42, 527.
14. Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.