Stereoselective synthesis of β-carboethoxy-γ-lactams via imino Mukaiyama aldol-type reaction of 1,4-bis(trimethylsilyloxy)-1,4-diethoxy-1,3-butadiene

Article abstract of DOI:10.1016/j.tet.2007.03.006

The reaction of the (bis)trimethylsilyloxy derivative of diethyl succinate with imines in the presence of ZnCl₂ provides a general stereoselective entry to β-carboethoxy-γ-lactams.

Full text of DOI:10.1016/j.tet.2007.03.006

Tetrahedron 63 (2007) 4328–4337
Stereoselective synthesis of b-carboethoxy-g-lactams via imino
Mukaiyama aldol-type reaction of 1,4-bis(trimethylsilyloxy)-
1
,4-diethoxy-1,3-butadiene
*
Manat Pohmakotr, Nattawut Yotapan, Patoomratana Tuchinda, Chutima Kuhakarn
*
and Vichai Reutrakul
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Received 28 November 2006; revised 15 February 2007; accepted 1 March 2007
Available online 6 March 2007
Abstract—The reaction of the (bis)trimethylsilyloxy derivative of diethyl succinate with imines in the presence of ZnCl
stereoselective entry to b-carboethoxy-g-lactams.
2
provides a general
Ó 2007 Elsevier Ltd. All rights reserved.
1
0
11
1
. Introduction
succinate with imine 2 in the presence of a Lewis acid
would lead to adduct 3, which should undergo subsequent
cyclisation to afford b-carboethoxy-g-lactam 4 (Scheme 1).
The g-lactam structure is an important subunit widely found
in many classes of nitrogen heterocycles. Moreover, this
1
class of compound can be utilised as a versatile starting
material for many synthetic manipulations. Numerous syn-
2
2. Results and discussion
thetic methods for the construction of g-lactams have been,
therefore, extensively investigated. The general methods
are based on Rh-catalysed intramolecular C–H insertion of
1,4-Bis(trimethylsilyloxy)-1,4-diethoxy-1,3-butadiene
was readily prepared according to Rathke’s procedure.
1
1
0
3
4
1
13
diazo derivatives, Pd-catalysed cyclisation, N-heterocyclic
carbene-catalysed addition of enals to imines, addition of
The H and C NMR spectra of 1 revealed that it was a mix-
ture of at least two geometrical isomers in the ratio of 2:3. In
the preliminary study, a search for a Lewis acid suitable for
promoting the reaction was carried out. A collection of
Lewis acids (BF $OEt , SnCl , Yb(OTf) , ZnBr and
5
6
7
homoenolates to imines, ring-expansion of b-lactams and
cycloaddition strategies.
8
3
2
4
3
2
In continuation of our work in developing new synthetic
methods using succinic ester derivatives as four-carbon
building blocks, it was anticipated that the reaction of
ZnCl ) was employed to mediate the reaction of (bis)tri-
2
1
0
methylsilyloxy derivative 1 derived from diethyl succinate
with imine 2g (Table 1). The best yield of lactam 4g
(48%) was obtained when the reaction was carried out in
9
(
bis)trimethylsilyloxy derivative 1 derived from diethyl
OTMS
OEt
O
EtO
OEt
2
EtO C
OTMS
EtO
1
) 1 M ZnCl2, THF
78 °C to rt
2) H O, 1 h
1
O
R2
O
R2
-
NH
R
N
+
3
R3
R3
N
2
R1
R1
R2
R1
3
4
H
2
Scheme 1.
*
0
Corresponding authors. Tel.: +66 2 201 5158; fax: +66 2 354 7151; e-mail addresses: scmpk@mahidol.ac.th; scvrt@mahidol.ac.th
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.006

M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
4329
Table 1. Lewis acid optimization
3f to the desired g-lactam 4f (90% yield, cis/trans¼20:80)
(J ¼9.3 Hz and J ¼5.8 Hz). The equivalent of base
Ph
H
cis
trans
N
EtO2C
OTMS
1
) Lewis acid, THF
O
(K CO ) employed is critical to the stereochemistry of the
2 3
-78 °C to rt
OEt
N
g-lactam. When an excess of K CO (3 equiv) was em-
2 3
ployed, a 10:90 ratio of cis- and trans-isomer 4f resulted.
This observation indicated that the cis-4f having a larger cou-
+
EtO
2
) H O, 1 h
Ph
2
OTMS
1
2g
4g
pling constant (J ¼9.3 Hz) was isomerised to a thermo-
cis
a
% Lactam 4a (cis/trans)
b
dynamically more stable trans-4f whose coupling constant
was smaller (Jtrans¼5.8 Hz). This experiment confirmed the
assigned stereochemistry of both cis- and trans-g-lactam 4.
Entry
Lewis acid
BF $OEt
1
2
3
4
5
3
2
36 (30:70)
27 (27:73)
36 (24:76)
41 (30:70)
48 (20:80)
SnCl
Yb(OTf)
ZnBr
ZnCl
4
3
With the optimum conditions established, we sought to
examine the reaction with other N-phenylimines. Therefore,
1 and 2g were subjected to the standard conditions, resulting
in a mixture of g-lactam 4g (48% yield, cis/trans¼20:80)
and uncyclised adduct 3g (32% yield, diastereomeric
ratio¼83:17) (Table 2, entry 7). To our surprise, the reaction
of 1 with N-phenylimine 2g gave the trans-g-lactam 4g as the
major isomer. It should be noted that, the stereochemical out-
comes are in sharp contrast to those observed when N-benzyl
imines were employed as imine partners. Treatment of the
crude mixture of 3g and 4g with anhydrous K CO (1 equiv)
2
2
a
Isolated yields.
b
1
Determined by integration of the H NMR (300 MHz) spectra of the crude
product.
the presence of ZnCl (Table 1, entry 5). Therefore, ZnCl
2
was chosen for further study in order to test the generality
of the reaction.
2
2
3
The scope of the Mukaiyama aldol-type reaction of 1,4-bis-
(trimethylsilyloxy)-1,4-diethoxy-1,3-butadiene 1 with a
range of imine derivatives was examined under the opti-
in refluxing ethanol furnished g-lactam 4g in 82% yield as
a 10:90 mixture of cis- and trans-isomer. As summarised in
Table 2 (entries 8–12), the mixtures of adducts 3h–k and
g-lactams 4h–k were afforded from the condensation of 1
with imines 2h–k, except for the reaction with 2l, where
only g-lactam 4l was obtained as the sole product (Table 2,
entry 12). The reactions of the mixtures of 3g/4g, 3j/4j and
mised conditions using ZnCl as a Lewis acid (Table 2).
2
Treatment of 1 (1 equiv), as a 2:3 mixture of stereoisomers,
with imine 2a (R ¼benzyl) (1 equiv) in THF in the presence
3
ꢀ
temperature overnight provided g-lactam 4a in 70% yield,
of ZnCl (1 equiv, 1 M solution in THF) at –78 C to room
2
3k/4k (Table 2, entries 7, 10 and 11) with anhydrous
K CO in absolute ethanol under reflux for 4 h led to com-
plete cyclisation and furnished the corresponding g-lactams
as a 90:10 mixture of cis- and trans-isomer (J ¼9.2 Hz
cis
2
3
1
2
and J ¼5.4 Hz) (Table 2, entry 1). No trace of the cor-
trans
responding b-lactam was observed. Similar results were ob-
tained when 1 was reacted with imines 2b–e to afford good
yields of the expected cis- and trans-g-lactam 4b–e (Table 2,
entries 2–5).
4
g (82% yield, cis/trans¼10:90), 4j (90% yield, cis/trans¼
0:100) and 4k (75% yield, cis/trans¼5:95), respectively.
At this point, on the basis of the stereochemistry seen in the
reactions summarised in Table 2, we shall advance a model
for the mechanism of Lewis acid mediated reactions of (bis)-
trimethylsilyloxy derivative 1 with N-phenyl imines and
N-benzyl imines. The transition state model employed to
explain the stereochemical outcomes observed in our study
However, the reaction of 1 with imine 2f under the same
conditions gave a mixture of g-lactam 4f (57% yield, cis/
trans¼75:25) and an uncyclised adduct 3f (33% yield, dia-
stereomeric ratio¼42:58). Fortunately, treatment of the
crude mixture of 3f (diastereomeric ratio¼42:58) and 4f
13
has been proposed based on previous report by Mukaiyama.
(
cis/trans¼75:25) with 1 equiv of K CO under refluxing
2
3
The work described Lewis base catalysed Mannich-type
reactions between trimethylsilyl enol ethers and N-tosyl
imines, irrespective of geometries of the silyl enol ethers,
to give the corresponding adducts with stereoconvergent
ethanol (4 h) led to complete cyclisation of the initial adduct
Table 2. Reaction of compound 1 with imines 2 catalysed by ZnCl
2
(
anti) selectivity.
a
a
Entry
Imine 2
% Lactam 4b
(cis/trans)
% Adduct 3
(diastereomeric
ratio)
1
R
2
R
3
R
The reaction was assumed to undergo via the staggered acy-
clic transition states. Selectivity was achieved by the steric
effect in the way that repulsion of the group attached to nitro-
gen atom and substituent of the enol ether being greater than
that of an aryl group of imine and the group on nitrogen atom.
2
b
1
2
3
4
5
6
7
8
9
2a
H
H
Bn 4a, 70 (90:10) 3a (—)
Bn 4b, 72 (90:10) 3b (—)
2b OMe
2c Cl
2d NO
H
H
H
Bn 4c, 76 (92:8)
Bn 4d, 70 (92:8)
3c (—)
3d (—)
2
In our current study, we employed Lewis acid (ZnCl ) to
2
catalyse the reaction. It is assumed that ZnCl occupies a co-
2
2e
2f
2g
H
OMe Bn 4e, 75 (85:15) 3e (—)
OMe OMe Bn 4f, 57 (75:25) 3f, 33 (42:58)
Ph 4g, 48 (20:80) 3g, 32 (83:17)
H
H
H
H
ordination site on the nitrogen atom such that it is cis to the
substituent at the imine carbon (Scheme 2). In the case of
N-benzyl imines, the selectivity was achieved by the steric
effect caused by the repulsive interaction of the benzyl group
and the substituent G of 1, leading preferably to anti-adduct 3
via transition state 5B (Scheme 2). This observation is anal-
2h Cl
Ph 4h, 48 (9:91)
Ph 4i, 16 (0:100)
OMe Ph 4j, 81 (25:75)
3h, 36 (60:40)
3i, 62 (50:50)
3j, 13 (42:58)
2i
2j
NO
2
10
11
12
H
2k OMe OMe Ph 4k, 33 (16:84) 3k, 53 (60:40)
3l (—)
2l
OMe
H
Ph 4l, 83 (20:80)
a
Isolated yields.
1
3
b
1
ogous to the results previously reported by Mukaiyama.
Except for 3f, most often, the firstly formed anti-adduct 3
Determined by integration of the H NMR (300 MHz) spectra of the crude
products.

4330
M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
Ph
ZnCl2
HO C
2
NHPh
Ar
EtO2C
H
H
Ar
4
N
H
H5
then H O
2.1% 4.9%
O
2
H
G
H
N
Ph
EtO2CH2C
H
N
Ph
O
Bn
H
Ar
4aA
CO2Et
syn-3
EtO
OTMS
trans-4
Figure 1.
5A
Bn
ZnCl2
NHBn
Ar
EtO2C
H
H
Ar
The cis or trans stereochemistry of g-lactam 4a was conclu-
sively established by the NOE experiment of the correspond-
ing carboxylic acid derivative 4aA of cis-g-lactam 4a, which
was obtained by hydrolysis of the 90:10 mixture of 4a
employing 6 M HCl in dioxane under reflux for 1 h (Fig. 1).
N
then H2O
H
H
H
H
G
CH2CO2Et
N
Bn
O
Ar
CO2Et
anti-3
TMSO
OEt
B
cis-4
5
OTMS
OEt
3
. Conclusion
G =
C
H
In conclusion, we have established an efficient stereoselec-
tive synthesis of g-lactams possessing b-carboethoxy group
by treatment of bis(trimethylsilyloxy) derivative of diethyl
Scheme 2.
succinate with imines catalysed by ZnCl . This type of
2
was not isolated but underwent cyclisation under the reaction
conditions to yield cis-g-lactam 4. Opposite stereoselectivity
was observed when N-phenyl imines were employed as the
reaction partners. This could be attributed to a greater steric
compound might be useful as starting materials in organic
synthesis. Simplicity of the procedure, readily available
starting materials and a possible stereocontrol of the reaction
are noteworthy. Work aimed at enantioselective synthesis of
this type of g-lactam is currently underway.
demanding of ZnCl causing 1,4-bis(trimethylsilyloxy)-1,4-
2
diethoxy-1,3-butadiene 1 to approach the N-phenyl imines
such that the substituent G being anti to the ZnCl (transition
2
state 5A, Scheme 2), leading to syn-adduct 3. However, due
to a poor nucleophilicity of the nitrogen atom of the N-phenyl
amine, cyclisation did not readily occur and a mixture of ad-
4. Experimental
4.1. General
1
4
duct 3 as a mixture of two diastereoisomers in varying ratio
1
13
and g-lactam 4 (favouring trans-isomer) was obtained. We
believed that cyclisation of the syn-adduct 3 to trans-g-lac-
tam 4 proceeded more rapidly than that of the anti-adduct 3
to cis-g-lactam 4. Therefore, the observed diastereoselectiv-
ity of adducts 3g–k in the N-phenyl series does not reflect the
cis/trans ratios of the g-lactams 4g–k. Attempted separation
of both isomers of 4a–f by preparative thin-layer chromato-
graphy (silica gel) was unsuccessful, except for cis-4a
wherein a white solid was obtained upon standing at room
temperature.
The H and C NMR spectra were recorded on Bruker
DPX-300 (300 MHz), Bruker DPX-400 (400 MHz) and
Bruker DPX-500 (500 MHz) spectrometers in CDCl using
3
tetramethylsilane as an internal standard. The chemical
shifts (d) reported are given in parts per million (ppm) and
the coupling constants (J) are in hertz (Hz). Melting points
were recorded on a Buchi 501 Melting Point Apparatus
and were uncorrected. The IR spectra were recorded on
a GX FTIR system Perkin–Elmer infrared spectrometer.
The EI mass spectra were recorded by using a Thermo
Finnigan Polaris Q mass spectrometer. The high-resolution
mass spectra were recorded on HR-TOF-MS Micromass
model at Chiangmai University. The elemental analyses
were performed by a Perkin–Elmer Elemental Analyzer
2400 CHN. Merck silica gel 60 PF254 was used for prepara-
tive thin-layer chromatography.
Ultimately, the isomerisation of cis-g-lactam to the thermo-
dynamically more stable trans-g-lactam was investigated.
Thus, treatment of a mixture of cis- and trans-g-lactam
4a–d and 4f with catalytic DBU in THF at room temperature
overnight furnished the trans-g-lactams 4a–d and 4f as the
major isomer. The results are listed in Table 3.
4
.2. Reaction of the 1,4-bis(trimethylsilyloxy)-1,4-
diethoxy-1,3-butadiene (1) with imines using ZnCl2
as a catalyst
Table 3. Equilibration of cis/trans mixture of g-lactam 4 employing DBU
(0.25 equiv) in THF at rt
a
b
% Yield of g-lactam 4 (trans/cis)
c
4.2.1. Ethyl 1-benzyl-5-oxo-2-phenylpyrrolidine-3-
carboxylate (4a).
g-Lactam 4 (cis/trans)
4
4
4
4
4
a (90:10)
b (90:10)
c (92:8)
d (92:8)
f (80:20)
80 (80:20)
85 (85:15)
80 (90:10)
60 (80:20)
70 (90:10)
4.2.1.1. General procedure. A mixture of imine 2a
0.195 g, 1 mmol) and zinc chloride solution (1 M in
(
THF, 1 mL) was added dropwise at –78 C to a solution of
ꢀ
1,4-bis(trimethylsilyloxy)-1,4-diethoxy-1,3-butadiene (1)
(
0.318 g, 1 mmol) in THF (2 mL) under an argon atmo-
a
b
c
Isolated products were used.
Isolated yields.
Determined by integration of the H NMR (300 MHz) spectra of the
isolated products.
sphere. The resulting mixture was slowly warmed up to
room temperature overnight (16 h). The resulting mixture
was quenched with H O, stirred to reach room temperature
1
2

M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
4331
for 1 h, and then extracted with EtOAc (3ꢁ30 mL). The
combined organic layers were washed with water, brine
and dried over anhydrous Na SO . After removal of solvent
135.6, 128.7 (cis- and trans-isomer), 128.6*, 128.4,
128.35*, 128.3, 128.1, 127.6*, 127.5, 127.4*, 114.3, 113.9*,
63.1, 61.7*, 61.2, 60.9*, 55.2, 55.16*, 46.1, 44.3*, 44.2,
2
4
under reduced pressure, a crude product 4a, which consisted
of a 90:10 mixture of cis/trans isomer, was purified by
preparative thin-layer chromatography (SiO , 20% EtOAc
2
42,9*, 33.6, 31.9*, 13.9, 13.6*. IR (KBr): n
(C]O of ester), 1675 (C]O of amide) cm . MS: m/z
1726
max
ꢂ1
+
+
(%) relative intensity 354 ([M+1] , 9), 353 ([M] , 18), 262
(100), 119 (23), 118 (25), 91 (84), 77 (10), 65 (13). HRMS
(ESI-TOF) calcd for C H NO Na [M+Na] : 376.1525;
in hexanes, triple runs) to give a 90:10 mixture of cis/trans
isomer of 4a (0.226 g, 70% yield). The pale yellow solid ob-
tained from PLC was recrystallised from i-PrOH–/hexanes
to give a white solid of a pure cis-4a isomer (0.203 g, 62%,
+
2
1
23
4
found: 376.1525.
ꢀ
mp 80–81 C) and a pale yellow oil of trans-4a (0.023 g, 8%
yield) contaminated with a small amount of cis-4a.
4.2.3. Ethyl 1-benzyl-2-(4-chlorophenyl)-5-oxopyrrol-
idine-3-carboxylate (4c). According to the general proce-
dure as described for compound 4a, a solution of 1
(0.318 g, 1 mmol) in THF (2 mL) was treated with imine
2c (0.229 g, 1 mmol) under an argon atmosphere. A crude
product 4c, which consisted of a 92:8 mixture of cis/trans iso-
mer, was purified by preparative thin-layer chromatography
1
4
.2.1.2. cis-4a. H NMR (300 MHz, CDCl ): d 7.40–7.20
3
(
(
m, 6H), 7.18–7.01 (m, 4H), 5.15 (d, J¼14.7 Hz, 1H), 4.63
d, J ¼9.2 Hz, 1H), 3.80–3.48 (m, 3H), 3.43 (d,
cis
J¼14.7 Hz, 1H), 3.21 (dd, J¼17.3, 10.2 Hz, 1H), 2.62 (dd,
1
3
J¼17.3, 9.2 Hz, 1H), 0.87 (t, J¼7.1 Hz, 3H). C NMR
(SiO , 20% EtOAc in hexanes, triple runs) to give a pale yel-
2
(
75 MHz, CDCl ): d 173.1, 169.9, 135.9, 135.7, 128.8,
3
low oil of product 4c (0.271 g, 76% yield, cis/trans¼92:8).
1
1
3
28.7, 128.6, 128.4, 127.7, 127.6, 62.2, 60.9, 44.5, 43.0,
1.9, 13.9. IR (CHCl ): n
H NMR (300 MHz, CDCl , cis-isomer marked as *):
3
1734 (C]O of ester), 1683
max
d 7.30–6.80 (m, 18H, ArH of cis- and trans-isomer), 5.08*
(d, J¼14.7 Hz, 1H), 5.03 (d, J¼14.7 Hz, 1H), 4.58* (d,
J ¼9.3 Hz, 1H), 4.49 (d, J ¼5.4 Hz, 1H), 4.05 (q,
3
ꢂ1
(
(
C]O of amide) cm . MS: m/z (%) relative intensity 324
+
+
[M+1] , 23), 323 ([M] , 6), 232 (100), 119 (18), 118 (32),
17 (13), 105 (6), 91 (27), 77 (4), 65 (6). Anal. Calcd for
C H NO : C, 74.28; H, 6.55; N, 4.33. Found: C, 74.57;
cis
trans
1
J¼7.1 Hz, 2H), 3.90–3.30* (m, 3H), 3.33 (d, J¼14.7 Hz,
2H, NCHHAr of cis- and trans-isomer), 2.55* (dd, J¼17.3,
9.4 Hz, 1H), 3.09* (dd, J¼17.3, 10.2 Hz, 1H), 3.10–2.85
2
0
21
3
H, 6.80; N, 4.44.
(
m, 1H), 2.85–2.60 (m, 2H), 1.09 (t, J¼7.1 Hz, 3H), 0.85*
1
13
4
.2.1.3. trans-4a. H NMR (300 MHz, CDCl ): d 7.35–
3
(t, J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl , cis-isomer
3
7
7
J
.25 (m, 3H), 7.25–7.15 (m, 3H), 7.15–7.01 (m, 2H),
.01–6.91 (m, 2H), 5.03 (d, J¼14.7 Hz, 1H), 4.53 (d,
¼5.4 Hz, 1H), 4.04 (q, J¼7.1 Hz, 2H), 3.41 (d,
marked as *): d 172.9*, 172.6, 172.8, 169.7*, 137.5,
135.6*, 135.3, 134.6*, 134.3 (cis- and trans-isomer), 129.3,
128.9, 128.8*, 128.7 (cis- and trans-isomer), 128.3*, 127.8*,
127.6, 62.9, 61.5*, 61.4, 60.9*, 46.0, 44.5*, 44.4, 42.8*, 33.4,
trans
J¼14.7 Hz, 1H), 3.20–2.60 (m, 3H), 1.09 (t, J¼7.1 Hz,
1
3
3
1
4
1
3
H). C NMR (75 MHz, CDCl ): d 172.9, 172.1, 138.9,
3
31.7*, 13.9, 13.6*. IR (neat): n 1724 (C]O of ester), 1678
max
ꢂ1
35.5, 129.1, 128.6, 128.4, 127.6, 126.9, 63.6, 61.3, 46.0,
4.4, 33.5, 14.0. IR (neat): n 1732 (C]O of ester),
695 (C]O of amide) cm . MS: m/z (%) relative intensity
(C]O of amide) cm . MS: m/z (%) relative intensity 358
+
+
([M+1] , 15), 357([M] , 7), 266 (100), 119 (28), 118 (33),
91 (50), 77 (4), 65 (14). HRMS (ESI-TOF) calcd for
C H NO ClNa [M+Na] : 380.1029; found: 380.1028.
max
ꢂ1
+
+
+
24 ([M+1] , 23), 323 ([M] , 6), 232 (100), 119 (18), 118
2
0
20
3
(
32), 117 (13), 105 (6), 91 (27), 77 (4), 65 (6). HRMS
ESI-TOF) calcd for C H NO [M+Na] : 346.1419;
+
(
found: 346.1415.
4.2.4. Ethyl 1-benzyl-2-(4-nitrophenyl)-5-oxopyrrol-
idine-3-carboxylate (4d). According to the general proce-
dure as described for compound 4a, a solution of 1 (0.318 g,
1 mmol) in THF (2 mL) was treated with imine 2d (0.241 g,
1 mmol) under an argon atmosphere. A crude product 4d,
which consisted of a 92:8 mixture of cis/trans isomer, was
purified by preparative thin-layer chromatography (SiO2,
20% EtOAc in hexanes, triple runs) to give a brown oil of
2
0
22
3
4
.2.2. Ethyl 1-benzyl-2-(4-methoxyphenyl)-5-oxopyrrol-
idine-3-carboxylate (4b). According to the general proce-
dure as described for compound 4a, a solution of 1 (0.318 g,
1
1
which consisted of a 90:10 mixture of cis/trans isomer,
was purified by preparative thin-layer chromatography
mmol) in THF (2 mL) was treated with imine 2b (0.225 g,
mmol) under an argon atmosphere. A crude product 4b,
1
product 4d (0.257 g, 70% yield, cis/trans¼92:8). H NMR
(300 MHz, CDCl , cis-isomer marked as *): d 8.20 (d,
3
(
yellow solid of product 4b (0.254 g, 72% yield, cis/
SiO , 20% EtOAc in hexanes, triple runs) to give a pale
J¼8.5 Hz, 4H, ArH of cis- and trans-isomer), 7.40–7.20
(m, 10H, ArH of cis- and trans-isomer), 7.15–7.00 (m, 4H
ArH of cis- and trans-isomer), 5.16* (d, J¼14.7 Hz, 1H),
2
ꢀ
1
trans¼90:10, mp¼55–56 C). H NMR (300 MHz, CDCl ,
3
cis-isomer marked as *): d 7.29–7.10 (m, 4H, ArH of cis-
and trans-isomer), 7.10–6.89 (m, 10H, ArH of cis- and
trans-isomer), 6.89–6.71 (m, 4H ArH of cis- and trans-iso-
mer), 5.07* (d, J¼14.7 Hz, 1H), 5.00 (d, J¼14.7 Hz, 1H),
5.00 (d, J¼14.7 Hz, 1H), 4.69* (d, J ¼9.4 Hz, 1H), 4.62
cis
(d, J ¼6.0 Hz, 1H), 4.05 (q, J¼7.1 Hz, 2H), 3.85–3.40*
trans
(m, 3H), 3.37 (d, J¼14.7 Hz, 2H, NCHHAr of cis- and
trans-isomer), 3.08* (dd, J¼17.4, 10.2 Hz, 1H), 2.57* (dd,
J¼17.4, 9.4 Hz, 1H), 3.10–2.85 (m, 1H), 2.85–2.65 (m,
4
4
3
.57* (d, J ¼9.3 Hz, 1H), 4.49 (d, J ¼5.8 Hz, 1H),
cis
trans
1
3
.05 (q, J¼7.1 Hz, 2H), 3.48–3.80* (m, 3H), 3.76 (s, 3H),
.73* (s, 3H), 3.35 (d, J¼14.7 Hz, 2H, NCHHAr of cis-
2H), 1.10 (t, J¼7.1 Hz, 3H), 0.93* (t, J¼7.1 Hz, 3H).
C
NMR (75 MHz, CDCl , cis-isomer marked as *): d 172.9*,
3
and trans-isomer), 3.00–2.90 (m, 1H), 2.85–2.65 (m, 2H),
172.7, 171.4, 169.4*, 148.1*, 146.4, 143.4 (cis- and trans-
isomer), 135.2*, 134.9, 128.9*, 128.7, 128.6 (cis- and
trans-isomer), 128.4*, 128.3, 128.0*, 127.9, 124.3, 123.8*,
62.8, 61.7, 61.5*, 61.2*, 45.8, 44.9*, 44.8, 42.8*, 33.3,
31.7*, 14.0, 13.7*. IR (neat): nmax 1732 (C]O of ester),
3
9
3
.18* (dd, J¼17.3, 10.3 Hz, 1H), 2.53* (dd, J¼17.3,
.3 Hz, 1H), 1.09 (t, J¼7.1 Hz, 3H), 0.85* (t, J¼7.1 Hz,
13
H). C NMR (75 MHz, CDCl , cis-isomer marked as *):
3
d 172.9*, 172.6, 172.1, 169.9*, 159.8*, 159.6, 135.9*,

4332
M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
ꢂ1
1
3
(
(
695 (C]O of amide) cm . MS: m/z (%) relative intensity
69 ([M+1] , 9), 368 ([M] , 13), 274 (100), 147 (30), 146
isomer), 127.9*, 127.6*, 127.5, 120.1*, 119.5, 111.2,
110.9*, 110.4*, 109.4, 63.6, 62.1*, 61.2, 60.8*, 55.84*,
55.8, 46.1, 44.45, 44.4*, 42.9*, 33.7, 31.9*, 14.0, 13.7*. IR
+
+
56), 119 (27), 118 (47), 116 (20), 115 (13), 106 (23), 104
52), 91 (80), 77 (8), 65 (20). Anal. Calcd for C H N O :
C, 64.21; H, 5.47; N, 7.60. Found: C, 64.24; H, 5.13; N, 7.75.
(CHCl ): n
1720 (C]O of ester), 1673 (C]O of
2
0
20
2
5
3
max
ꢂ1
amide) cm . MS: m/z (%) relative intensity 384 ([M+1] ,
+
+
23), 383 ([M] , 6), 292 (58), 149 (66), 146 (28), 119 (22),
118 (23), 104 (12), 91 (100), 77 (32), 65 (26), 55 (44).
HRMS (ESI-TOF) calcd for C H NO Na [M+Na] :
2
4
.2.5. Ethyl 1-benzyl-2-(3-methoxyphenyl)-5-oxopyrrol-
idine-3-carboxylate (4e). According to the general proce-
dure as described for compound 4a, a solution of 1
+
2
25
5
408.1630; found: 408.1630.
(
2
0.318 g, 1 mmol) in THF (2 mL) was treated with imine
e (0.225 g, 1 mmol) under an argon atmosphere. A crude
product 4e, which consisted of an 85:15 mixture of cis/trans
1
4.2.6.2. Succinate 3f. H NMR(300 MHz, CDCl , minor-
3
isomer marked as *): d 7.00 (t, J¼8.1 Hz, 4H, ArH of major-
and minor-isomer), 6.80–6.68 (m, 6H, ArH of major- and
minor-isomer), 6.60–6.50 (m, 2H, ArH of major- and mi-
nor-isomer), 6.50–6.39 (m, 4H ArH of major- and minor-iso-
isomer, was purified by preparative thin-layer chromato-
graphy (SiO , 20% EtOAc in hexanes, triple runs) to give
2
a pale yellow solid of product 4e (0.264 g, 75% yield, cis/
ꢀ
1
trans¼85:15, mp¼160–164 C). H NMR (300 MHz,
mer), 4.63* (d, Jminor¼5.4 Hz, 1H), 4.45 (d, J
¼6.8 Hz,
major
CDCl , cis-isomer marked as *): d 7.30–6.53 (m, 18H, ArH
3
1H), 4.09–3.95 (m, 8H, OCH CH of major- and minor-iso-
2 3
of cis- and trans-isomer), 5.10* (d, J¼14.7 Hz, 1H), 5.02
mer), 3.77 (s, 16H, OCH and NCH Ar of major- and minor-
3 2
(
d, J¼14.7 Hz, 1H), 4.58 (d, J¼9.2 Hz, 1H), 4.51* (d,
isomer), 3.26–3.20 (m, 1H), 3.20–3.10* (m, 1H), 2.74 (dd,
J¼17.1, 10.1 Hz, 2H, CHCHHCO of major- and minor-
isomer), 2.45–2.32 (m, 2H, CHCHHCO of major- and
minor-isomer), 1.22–1.02 (m, 12H, OCH CH of major-
J¼5.5 Hz, 1H), 4.05 (q, J¼7.1 Hz, 2H), 3.80–3.25* (m,
H), 3.81* (s, 3H), 3.83 (s, 3H), 3.37 (d, J¼14.7 Hz, 2H,
NCHHAr of cis- and trans-isomer), 3.21* (dd, J¼17.3,
3
2
3
1
3
1
0.2 Hz, 1H), 2.55* (dd, J¼17.3, 9.3 Hz, 1H), 3.10–2.85
and minor-isomer). C NMR (75 MHz, CDCl , minor-
3
(
(
m, 1H), 2.85–2.65 (m, 2H), 1.16 (t, J¼7.1 Hz, 3H), 0.87*
isomer marked as *): d 173.3, 172.7*, 172.0*, 171.6, 149.2,
149.1*, 148.4, 146.8*, 146.7 (major- and minor-isomer),
133.0, 132.3*, 129.04, 129.0*, 119.1, 119.0*, 117.8*,
117.6, 113.7*, 113.4, 111.14*, 111.1, 109.7*, 109.5, 61.1*,
61.0, 60.8, 60.3*, 58.7, 58.6*, 55.85, 55.8*, 48.1, 48.0*,
1
3
t, J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl , cis-isomer
3
marked as *): d 173.1*, 172.8, 172.1, 169.9*, 160.2,
1
1
1
5
1
59.7*, 140.6, 137.3*, 135.9*, 135.6, 130.2*, 129.7, 128.6*,
28.5, 128.43*, 128.40, 127.7*, 127.6, 119.8*, 119.0,
13.9*, 113.86, 113.3*, 112.3, 63.5, 62.1*, 61.3, 60.8*,
5.24, 55.2*, 45.8, 44.5*, 44.4, 42.9*, 33.5, 31.9*, 14.0,
44.45, 44.4*, 34.8, 32.1*, 14.03, 14.0*. IR (neat): n
3395 (N–H), 1732 (C]O of ester) cm . MS: m/z (%) rela-
max
ꢂ1
+
3.6. IR (neat): n
1732 (C]O of ester), 1695 (C]O of
tive intensity 429 ([M] , 0.05), 242 (100), 104 (32), 91 (1), 77
(10). HRMS (ESI-TOF) calcd for C H NO [M] :
429.2151; found: 429.2150.
max
ꢂ1
+
+
amide) cm . MS: m/z (%) relative intensity 354 ([M+1] ,
2
4
31
6
+
23), 353 ([M] , 6), 225 (50), 147 (39), 146 (28), 119 (28),
118 (51), 104 (34), 91 (100), 77 (18), 65 (25). HRMS (ESI-
+
TOF) calcd for C H NO [M+1] : 354.1705; found:
24
4.2.7. Ethyl 5-oxo-1,2-diphenylpyrrolidine-3-carboxylate
(4g) and diethyl 2-(phenyl(phenylamino)methyl)succi-
nate (3g). According to the general procedure as described
for compound 4a, a solution of 1 (0.318 g, 1 mmol) in
THF (2 mL) was treated with imine 2g (0.181 g, 1 mmol)
under an argon atmosphere. A crude product 4g was purified
2
1
4
3
54.1705.
4
.2.6. Ethyl 1-benzyl-2-(3,4-dimethoxyphenyl)-5-oxopyr-
rolidine-3-carboxylate (4f) and diethyl 2-[(benzylamino)-
3,4-dimethoxyphenyl)methyl]succinate (3f). According
(
to the general procedure as described for compound 4a, a
solution of 1 (0.318 g, 1 mmol) in THF (2 mL) was treated
with imine 2f (0.255 g, 1 mmol) under an argon atmosphere.
A crude product 4f was purified by preparative thin-layer
by preparative thin-layer chromatography (SiO , 20%
2
EtOAc in hexanes, triple runs) to give a pure trans-isomer
(0.110 g, 36% yield as a pale yellow solid, mp¼115–
ꢀ
of 4g, and an adduct 3g (0.113 g, 32% yield) as an 83:17
mixture of isomers.
116 C) and cis-isomer (38 mg, 12% yield as a yellow oil)
chromatography (SiO , 20% EtOAc in hexanes, triple
2
runs) to give a pale yellow oil of a 75:25 mixture of cis/trans
isomer of product 4f (0.218 g, 57% yield cis/trans¼75:25)
and an adduct 3f (0.141 g, 33% yield) as a 42:58 mixture
of isomers.
1
4.2.7.1. trans-4g. H NMR (300 MHz, CDCl ): d 7.39 (d,
3
J¼7.6 Hz, 2H), 7.35–7.19 (m, 7H), 7.06 (t, J¼7.5 Hz, 1H),
13
5
.53 (d, J ¼4.6 Hz, 1H), 4.22 (q, J¼7.1 Hz, 2H), 3.20–
trans
1
4
.2.6.1. Carboxylate 4f. H NMR (300 MHz, CDCl cis-
3
2.80 (m, 3H), 1.27 (t, J¼7.1 Hz, 3H). C NMR (75 MHz,
,
isomer marked as *): d 7.30–6.53 (m, 16H, ArH of cis- and
trans-isomer), 5.05* (d, J¼14.6 Hz, 1H), 4.96 (d,
J¼14.6 Hz, 1H), 4.56* (d, J¼9.3 Hz, 1H), 4.47 (d,
J¼6.0 Hz, 1H), 4.02 (q, J¼7.1 Hz, 2H), 3.30–3.90* (m,
CDCl ): d 172.15, 172.1, 139.7, 137.5, 129.0, 128.7,
3
128.2, 126.1, 125.3, 122.7, 65.8, 61.6, 46.4, 34.3, 14.1. IR
(CHCl ): n
1731 (C]O of ester), 1698 (C]O of
max
3
ꢂ1
+
amide) cm . MS: m/z (%) relative intensity 310 ([M+1] ,
24), 309 ([M] , 97), 236 (100), 208 (99), 180 (71), 91
+
3
H), 3.82 (s, 3H), 3.80* (s, 3H), 3.74 (s, 6H, OCH of cis-
3
and trans-isomer), 3.37 (d, J¼14.6 Hz, 2H, NCHHAr of
(24), 77 (38), 50 (11). Anal. Calcd for C H NO : C,
1
73.77; H, 6.19; N, 4.53. Found: C, 73.79; H, 6.25; N, 4.41.
9
19
3
cis- and trans-isomer), 3.21* (dd, J¼17.3, 10.1 Hz, 1H),
2
2
3
.55* (dd, J¼17.3, 9.4 Hz, 1H), 3.05–2.85 (m, 1H), 2.85–
1
.65 (m, 2H), 1.10 (t, J¼7.1 Hz, 3H), 0.84* (t, J¼7.1 Hz,
4.2.7.2. cis-4g. H NMR (300 MHz, CDCl ): d 7.42 (d,
3
1
3
H). C NMR (75 MHz, CDCl , cis-isomer marked as *):
3
J¼7.9 Hz, 2H) 7.35–7.10 (m, 7H), 7.06 (t, J¼7.3 Hz, 1H),
d 172.9*, 172.6, 172.1, 170.0*, 149.4, 149.2*, 149.1, 149.0*,
35.9*, 135.7, 131.0, 128.6*, 128.4, 128.37 (cis- and trans-
5.48 (d, J ¼8.8 Hz, 1H), 3.88–3.65 (m, 3H), 3.32 (dd,
cis
1
J¼17.3, 10.2 Hz, 1H), 2.72 (dd, J¼17.3, 8.8 Hz, 1H), 0.99

M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
4333
1
3
ꢂ1
of ester), 1698 (C]O of amide) cm . MS: m/z (%) relative
(
1
1
(
(
t, J¼7.2 Hz, 3H). C NMR (75 MHz, CDCl ): d 172.7,
3
+
+
69.5, 137.8, 136.2, 128.7, 128.62, 128.6, 127.0, 125.3,
22.1, 65.1, 61.0, 43.7, 32.9, 13.7. IR (neat): nmax 1732
C]O of ester), 1707 (C]O of amide) cm . MS: m/z
%) relative intensity 310 ([M+1] , 29), 309 ([M] , 75),
81 (51), 236 (100), 208 (78), 91 (21), 77 (33), 65 (3).
HRMS (ESI-TOF) calcd for C H NO Na [M+Na] :
intensity 344 ([M+1] , 21), 343 ([M] , 93), 270 (90), 242
(100), 216 (71), 91 (9), 77 (53), 50 (12). HRMS (ESI-TOF)
calcd for C H NO Cl [M+1] : 344.1503; found: 344.1502.
ꢂ1
+
1
9
19
3
+
+
1
2
4.2.8.3. Succinate 3h. H NMR (400 MHz, CDCl3,
minor-isomer marked as *): d 7.40–7.20 (m, 8H, ArH of
major- and minor-isomer), 7.09 (t, J¼8.0 Hz, 4H, ArH of
major- and minor-isomer), 6.67 (t, J¼6.8 Hz, 4H, ArH
of major- and minor-isomer), 6.65 (t, J¼7.3 Hz, 2H, ArH
+
1
9
19
3
3
32.1263; found: 332.1263.
1
4
.2.7.3. Succinate 3g. H NMR (300 MHz, CDCl , mi-
3
nor-isomer marked as *): d 7.40–6.40 (m, 20H, ArH of ma-
jor- and minor-isomer), 4.67* (d, Jminor¼5.5 Hz, 1H), 4.52
of major- and minor-isomer), 4.78 (d, J
¼5.6 Hz, 1H),
2 3
major
4.63* (d, Jminor¼5.6 Hz, 1H), 4.20–4.05 (m, 8H, OCH CH
(
d, Jmajor¼6.5 Hz, 1H), 4.10–3.90 (m, 8H, OCH CH of
of major- and minor-isomer), 3.45–3.35* (m, 1H), 3.35–3.25
(m, 1H), 2.91–2.80 (m, 2H, CHCHHCO of major- and
minor-isomer), 2.60–2.40 (m, 2H, CHCHHCO of major-
and minor-isomer), 1.22 (t, J¼7.1 Hz, 6H, OCH CH of
2
3
major- and minor-isomer), 3.35–3.20* (m, 1H), 3.20–3.10
m, 1H), 2.85–2.70 (m, 2H, CHCHHCO of major- and mi-
(
nor-isomer), 2.45–2.30 (m, 2H, CHCHHCO of major- and
minor-isomer), 1.12 (t, J¼7.1 Hz, 6H, OCH CH of major-
2
3
major- and minor-isomer), 1.13 (t, J¼7.1 Hz, 6H, OCH CH
2
3
2
3
1
3
and minor-isomer), 1.03 (t, J¼7.1 Hz, 6H, OCH CH of
of major- and minor-isomer). C NMR (125 MHz, CDCl ,
3
2
3
13
major- and minor-isomer). C NMR (75 MHz, CDCl , minor-
3
minor-isomer marked as *): d 173.9*, 173.3, 172.7, 172.2*,
147.3*, 147.15, 141.1 (major- and minor-isomer), 140.6
(major- and minor-isomer), 129.8*, 129.7, 129.3 (major-
and minor-isomer), 128.3 (major- and minor-isomer),
127.5, 127.4*, 118.5*, 118.3, 114.4, 114.1*, 61.8, 61.7*,
61.5 (major- and minor-isomer), 59.5, 59.4*, 48.6 (major-
and minor-isomer) 35.2*, 32.8, 14.7 (major- and minor-
isomer marked as *): d 173.2, 172.6*, 172.0*, 171.5, 146.6*,
1
46.5, 140.4, 139.8*, 129.1, 129.0*, 128.6 (major- and minor-
isomer), 127.5 (major- and minor-isomer), 126.8*, 126.7,
17.8, 117.5*, 113.6*, 113.3, 61.1*, 61.0, 60.8 (major- and
minor-isomer), 58.7 (major- and minor-isomer), 48.0,
7.9*, 34.5, 32.0*, 14.04 (major- and minor-isomer), 13.96
1
4
(
1
3
major- and minor-isomer). IR (neat): nmax 3386 (N–H),
isomer), 14.66 (major- and minor-isomer). IR (neat): n
3396 (N–H), 1731(C]O of ester) cm . MS: m/z (%) rela-
max
ꢂ1
ꢂ1
+
734 (C]O of ester) cm . MS: m/z (%) relative intensity
56 ([M+1] , 8), 355 ([M] , 1), 182 (100), 180 (4), 104
+
+
+
tive intensity 401 ([M+1] , 6), 400 ([M] , 4), 227 (100), 212
(50), 104 (15), 91 (2), 77 (11). HRMS (ESI-TOF) calcd for
C H NO Cl [M+1] : 390.1472; found: 390.1471.
(16), 91 (1), 77 (12). HRMS (ESI-TOF) calcd for
C H O Na [M+Na] : 356.1862; found: 356.1862.
+
+
2
2
25
5
21 25
4
4
.2.8. Ethyl 2-(4-chlorophenyl)-5-oxo-1-phenylpyrrol-
idine-3-carboxylate (4h) and diethyl 2-[(4-chlorophenyl)-
phenylamino)methyl]succinate (3h). According to the
4.2.9. Ethyl 2-(4-nitrophenyl)-5-oxo-1-phenylpyrrol-
idine-3-carboxylate (4i) and diethyl 2-((4-nitrophenyl)-
(phenylamino)methyl)succinate (3i). According to the
general procedure as described for compound 4a, a solution
of 1 (0.318 g, 1 mmol) in THF (2 mL) was treated with
imine 2i (0.226 g, 1 mmol) under an argon atmosphere. A
crude product 4i was purified by preparative thin-layer chro-
(
general procedure as described for compound 4a, a solution
of 1 (0.318 g, 1 mmol) in THF (2 mL) was treated with
imine 2h (0215 g, 1 mmol) under an argon atmosphere. A
crude product 4h was purified by preparative thin-layer
chromatography (SiO , 20% EtOAc in hexanes, triple
2
matography (SiO , 20% EtOAc in hexanes, triple runs) to
2
runs) to give a pure trans-isomer (0.141 g, 41% yield, as
a pale yellow solid, mp¼117–119 C) and cis-isomer
give a pure trans-isomer 4i (58 mg, 16% yield, as a pale
yellow solid, mp¼132–133 C) and an adduct 3i (0.248 g,
ꢀ
27 mg, 7% yield, as a yellow oil) product of 4h, and an
ꢀ
62% yield, as a 50:50 mixture of isomers).
(
adduct 3h (0.140 g, 36% yield as a 60:40 mixture of isomers).
1
4
.2.9.1. trans-4i. H NMR (300 MHz, CDCl ): d 8.08 (d,
3
1
4.2.8.1. trans-4h. H NMR (300 MHz, CDCl ): d 7.27
m, 2H), 7.20–7.05 (m, 6H), 7.01 (m, 1H), 5.44 (d,
J¼8.6 Hz, 2H), 7.38 (d, J¼8.6 Hz, 2H), 7.35–7.10 (m, 4H),
3
(
7.02 (m, 1H), 5.60 (d, J ¼5.1 Hz, 1H), 4.17 (q, J¼7.1 Hz,
trans
1
3
Jtrans¼4.8 Hz, 1H), 4.15 (q, J¼7.1 Hz, 2H), 3.00–2.70 (m,
2H), 3.10–2.81 (m, 3H), 1.22 (t, J¼7.1 Hz, 3H). C NMR
1
3
3
d 171.8, 138.2, 137.1, 134.0, 129.2, 128.8, 127.7, 125.6,
H), 1.20 (t, J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl ):
(75 MHz, CDCl ): d 171.6, 171.4, 147.7, 147.0, 137.0,
3
3
129.0, 127.3, 125.9, 124.3, 122.6, 64.7, 62.0, 46.1, 34.3,
14.1. IR (neat): n
1
(
22.7, 65.0, 61.7, 46.4, 34.3, 14.1. IR (neat): nmax 1731
C]O of ester), 1714 (C]O of amide) cm . MS: m/z
1731 (C]O of ester), 1714 (C]O of
max
ꢂ1
ꢂ1
+
amide) cm . MS: m/z (%) relative intensity 354 ([M] , 1),
242 (100), 216 (59), 91 (15), 77 (92), 55 (10). Anal. Calcd
for C H N O : C, 64.21; H, 5.47; N, 7.60. Found: C,
+
+
(
2
(
%) relative intensity 344 ([M+1] , 16), 343 ([M] , 68),
70 (83), 242 (100), 240 (23), 216 (59), 91 (9), 77 (81), 55
12). Anal. Calcd for C H NO Cl: C, 66.38; H, 5.28; N,
1
9 18 2 5
64.24; H, 5.13; N, 7.75.
1
9
18
3
4
.07. Found: C, 66.17; H, 4.92; N, 4.00.
1
4
.2.9.2. Succinate 3i. H NMR (400 MHz, CDCl , one
3
1
4.2.8.2. cis-4h. H NMR (300 MHz, CDCl ): d 7.32 (m,
H), 7.21–7.16 (m, 4H), 7.16–6.95 (m, 3H), 5.41 (d,
isomer marked as *): d 8.19 (d, J¼8.8 Hz, 4H, ArH of both
isomers), 7.53 (m, 4H, ArH of both isomers), 7.10 (m, 4H,
ArH of both isomers), 6.70 (q, J¼7.2 Hz, 2H, ArH of both
isomers), 6.47 (m, 4H, ArH of both isomers), 5.10*
(br, 1H), 4.75 (br, 1H), 4.86 (d, Jmajor¼5.3 Hz, 1H), 4.79*
(d, Jminor¼5.1 Hz, 1H), 4.05–4.20 (m, 8H, OCH CH of
3
2
J ¼8.8 Hz, 1H), 3.90–3.60 (m, 3H), 3.22 (dd, J¼17.3,
cis
1
0.5 Hz, 1H), 2.67 (dd, J¼17.3, 9.3 Hz, 1H), 0.96 (t,
3
1
3
J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl ): d 172.4,
1
6
69.4, 137.4, 134.8, 134.5, 128.6, 128.4, 125.5, 122.1,
4.4, 61.2, 43.4, 32.8, 13.7. IR (CHCl ): nmax 1732 (C]O
2
3
both isomers), 3.30–3.43 (m, 2H, CH CHCO Et of both
2 2
3

4334
M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
isomers), 2.90 (dd, J¼17.0, 8.2 Hz, 1H), 2.84* (dd, J¼17.0,
isomer), 3.30–3.20* (m, 1H), 3.20–3.10 (m, 1H), 2.80–2.60
(m, 2H, CHCHHCO of major- and minor-isomer), 2.40–2.25
(m 2H, CHCHHCO of major- and minor-isomer), 1.15–
9
.5 Hz, 1H), 2.66* (dd, J¼17.0, 5.6 Hz, 1H), 2.43 (dd,
J¼17.0, 4.8 Hz, 1H), 1.23* (t, J¼7.1 Hz, 3H), 1.22 (t,
J¼7.1 Hz, 3H), 1.15 (t, J¼7.1 Hz, 3H), 1.10* (t, J¼7.1 Hz,
1
3
0.90 (m, 12H, OCH CH of major- and minor-isomer).
C
NMR (75 MHz, CDCl , both isomers): d 173.9, 172.2,
2
3
1
3
3H). C NMR (125 MHz, CDCl one isomer marked as *):
d 173.2*, 172.6, 172.3, 171.9*, 149.3*, 148.5, 148.2,
3
,
3
160.5, 147.2, 143.0, 130.3, 129.7, 119.8, 118.2, 114.0,
113.5, 113.2, 61.7, 61.5, 59.5, 55.8, 48.6, 35.2, 14.7, 14.6.
IR (neat): nmax 3385 (N–H), 1721 (C]O of ester) cm . MS:
1
1
48.1*, 146.6*, 146.5, 130.0*, 129.9, 128.6, 128.4*, 124.6,
24.5*, 119.2, 118.9*, 114.3, 113.9*, 62.2, 62.0*, 61.7
ꢂ1
+
+
(
both isomers), 59.1, 58.5*, 48.13, 48.07*, 35.0*, 32.8,
m/z (%) relative intensity 386 ([M+1] , 32), 385 ([M] , 4), 215
(100), 104 (26), 91 (3), 77 (16). HRMS (ESI-TOF) calcd
1
3
4.7 (both isomers), 14.6 (both isomers). IR (neat): nmax
400 (N–H), 1731 (C]O of ester) cm . MS: m/z (%) rela-
ꢂ1
+
+
for C H NO [M+1] : 386.1969; found: 386.1967.
2
2
28
5
+
tive intensity 401 ([M+1] , 6), 400 ([M] , 4), 227 (100), 212
50), 104 (15), 91 (2), 77 (11). HRMS (ESI-TOF) calcd for
C H N O ClNa [M+Na] : 423.1532; found: 423.1531.
(
4.2.11. Preparation of ethyl 2-(3,4-dimethoxyphenyl)-5-
oxo-1-phenylpyrrolidine-3-carboxylate (4k) and diethyl
+
2
1 24 2 5
2
-[(3,4-dimethoxyphenyl)(phenylamino)methyl]succi-
4
.2.10. Ethyl 2-(3-methoxyphenyl)-5-oxo-1-phenylpyr-
nate (3k). According to the general procedure as described
for compound 4a, a solution of 1 (0.318 g, 1 mmol) in
THF (2 mL) was treated with imine 2k (0.242 g, 1 mmol)
under an argon atmosphere. A crude product 4k was purified
rolidine-3-carboxylate (4j) and diethyl 2-[(3-methoxy-
phenyl)(phenylamino)methyl]succinate (3j). According to
the general procedure as described for compound 4a, a solu-
tion of 1 (0.318 g, 1 mmol) in THF (2 mL) was treated with
imine 2j (0.211 g, 1 mmol) under an argon atmosphere. A
crude product 4j was purified by preparative thin-layer chro-
by preparative thin-layer chromatography (SiO , 20%
2
EtOAc in hexanes, triple runs) to give a pure trans-isomer
(0.099 g, 26% yield, as a pale yellow solid, mp¼136–
ꢀ
of product 4k, and an adduct 3k (0.220 g, 53% yield as
a 60:40 mixture of isomers).
matography (SiO , 20% EtOAc in hexanes, triple runs) to
2
137 C) and cis-isomer (28 mg, 7% yield, as a yellow oil)
give a pure trans-isomer (0.205 g, 61% yield, as a pale yel-
ꢀ
low solid, mp¼117–119 C) and cis-isomer (69 mg, 20%
yield, as a yellow oil) of product 4j (0.274 g, 81% yield),
and an adduct 3j (50 mg, 13% yield as a 42:58 mixture of
isomers).
1
4.2.11.1. trans-4k. H NMR (300 MHz, CDCl ): d 7.29
3
(d, J¼8.4 Hz, 2H), 7.20–6.90 (m, 4H), 6.80–6.50 (m, 2H),
5
(s, 3H), 3.72 (s, 3H), 2.78–3.08 (m, 3H), 1.21 (t,
.39 (d, J ¼5.0 Hz, 1H), 4.15 (q, J¼7.1 Hz, 2H), 3.75
trans
1
4
.2.10.1. trans-4j. H NMR (300 MHz, CDCl ): d 7.32 (d,
3
1
3
J¼7.7 Hz, 2H), 7.30–7.10 (m, 3H), 7.00 (t, J¼7.3 Hz, 1H),
J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl ): d 177.3,
3
6
.80–6.50 (m, 3H), 5.42 (d, J ¼4.5 Hz, 1H), 4.15 (q,
172.0, 149.4, 148.8, 137.5, 132.0, 128.7, 125.5, 122.9,
118.7, 111.3, 108.9, 66.0, 61.6, 55.9, 55.8, 46.7, 34.5,
trans
J¼7.1 Hz, 2H), 3.66 (s, 3H), 2.80–3.10 (m, 3H), 1.21 (t,
1
3
J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl ): d 172.2,
14.1. IR (CHCl ): n
3
1731 (C]O of ester), 1695 (C]O
max
3
ꢂ1
1
1
72.1, 160.0, 141.4, 137.5, 130.2, 128.8, 125.4, 122.7,
18.3, 113.4, 111.9, 65.8, 61.7, 55.2, 46.7, 34.4, 14.2. IR
of amide) cm . MS: m/z (%) relative intensity 371
+
+
+
([M+2] , 6), 370 ([M+1] , 24), 369 ([M] , 100), 240 (57),
91 (12), 77 (22). HRMS (ESI-TOF) calcd for C H NO Na
[M+Na] : 392.1474; found: 392.1477.
(neat): nmax 1732 (C]O of ester), 1706 (C]O of
amide) cm . MS: m/z (%) relative intensity 340 ([M+1] ,
7
HRMS (ESI-TOF) calcd for C H NO [M+1] :
21
23
5
ꢂ1
+
+
+
), 339 ([M] , 76), 210 (100), 91 (31), 77 (78), 55 (12).
+
1
4.2.11.2. cis-4k. H NMR (300 MHz, CDCl ): d 7.41 (d,
3
2
0
22
4
3
40.1549; found: 340.1545.
J¼8.1 Hz, 2H), 7.26 (t, J¼6.7 Hz, 2H), 7.09 (t, J¼7.4 Hz,
1
3.75–3.95 (m, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.31 (dd,
H), 6.70 (s, 2H), 6.67 (s, 1H), 5.43 (d, J ¼8.8 Hz, 1H),
cis
1
4
.2.10.2. cis-4j. H NMR (300 MHz, CDCl ): d 7.36 (d,
3
J¼8.3 Hz, 2H), 7.25–7.05 (m, 3H), 7.01 (t, J¼7.3 Hz, 1H),
J¼17.3, 10.0 Hz, 1H), 2.72 (dd, J¼17.3, 8.9 Hz, 1H), 1.03
1
3
6
.80–6.60 (m, 3H), 5.37 (d, J ¼8.8 Hz, 1H), 3.90–3.60
(t, J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl ): d 172.7,
cis
3
(
m, 3H), 3.67 (s, 3H), 3.24 (dd, J¼17.3, 10.8 Hz, 1H),
169.7, 149.2, 149.1, 137.9, 128.8, 128.6, 125.4, 122.3,
119.6, 111.1, 110.1, 65.0, 55.9, 55.8, 43.8, 33.1, 29.7,
1
3
2 C
NMR (75 MHz, CDCl ): d 172.7, 169.5, 159.8, 137.8,
.64 (dd, J¼17.3, 8.8 Hz, 1H), 0.96 (t, J¼7.1 Hz, 3H).
13.8. IR (CHCl ): n
3
1731 (C]O of ester), 1696 (C]O
max
3
ꢂ1
1
5
29.7, 128.8, 125.3, 122.1, 119.2, 113.6, 113.0, 65.0, 61.1,
5.2, 43.7, 33.0, 13.8. IR (CHCl ): n
of amide) cm . MS: m/z (%) relative intensity 371
+
+
+
1736 (C]O of
max
([M+2] , 7), 370 ([M+1] , 37), 369 ([M] , 100), 91 (12),
77 (30). HRMS (ESI-TOF) calcd for C H NO Na
[M+Na] : 392.1474; found: 392.1477.
3
ꢂ1
ester), 1697 (C]O of amide) cm . MS: m/z (%) relative
2
1
23
5
+
+
+
intensity 340 ([M+1] , 21), 339 ([M] , 100), 266 (92), 91
11), 77 (29), 55 (6). HRMS (ESI-TOF) calcd for
C H NO [M+1] : 340.1549; found: 340.1550.
(
+
1
4.2.11.3. Succinate 3k. H NMR (400 MHz, CDCl ,
3
2
0
22
4
minor-isomer marked as *): d 7.00 (t, J¼8.1 Hz, 4H, ArH
of major- and minor-isomer), 6.80–6.68 (m, 6H, ArH of
major- and minor-isomer), 6.60–6.50 (m, 2H, ArH of major-
and minor-isomer), 6.50–6.39 (m, 4H, ArH of major- and mi-
nor-isomer), 4.63 (d, J¼5.4 Hz, 1H), 4.45* (d, J¼6.9 Hz,
1H), 4.85 (br, 1H, NH of major- and minor-isomer), 4.09
(q, J¼7.1 Hz, 4H), 4.08* (q, J¼7.1 Hz, 4H), 3.84 (s, 12H,
1
4
.2.10.3. Succinate 3j. H NMR (300 MHz, CDCl , mi-
3
nor-isomer marked as *): d 7.09 (t, J¼8.3 Hz, 4H, ArH of
major- and minor-isomer), 6.94 (t, J¼7.6 Hz, 4H, ArH of
major- and minor-isomer), 6.90–6.45 (m, 8H, ArH of major-
and minor-isomer), 6.39 (t, J¼7.3 Hz, 2H, ArH of major-
and minor-isomer), 4.62* (d, J
¼5.3 Hz, 1H), 4.44 (d,
2 3
minor
Jmajor¼6.8 Hz, 1H), 4.10–3.90 (m, 8H, OCH CH of major-
OCH of major- and minor-isomer), 3.40–3.30* (m, 1H),
3
and minor-isomer), 3.37 (s, 6H, OCH of major- and minor-
3
3.30–3.20 (m, 1H), 2.74 (dd, J¼17.1, 10.1 Hz, 1H,

M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
4335
CHCHHCO of major- and minor-isomer), 2.45–2.32 (m,
CHCHHCO of major- and minor-isomer), 1.21* (t,
J¼7.1 Hz, 3H), 1.20 (t, J¼7.1 Hz, 3H), 1.16 (t, J¼7.1 Hz,
(3ꢁ20 mL). The combined organic layers were washed
with water and brine, and dried over anhydrous Na SO . Af-
2
4
ter removal of solvent under reduced pressure, a crude prod-
uct was purified by preparative thin-layer chromatography
(SiO , 20% EtOAc in hexanes, triple runs) to give a mixture
1
3
3
H), 1.15* (t, J¼7.1 Hz, 3H). C NMR (125 MHz, CDCl ,
3
minor-isomer marked as *): d 174.0*, 173.4, 172.7, 171.3*,
2
1
1
1
49.85*, 149.8, 149.05*, 149.0, 147.4, 147.3*, 133.7*,
33.0, 129.73*, 129.7, 119.8*, 119.7, 118.5, 118.3*, 114.4,
14.1*, 111.8, 111.76*, 110.4, 110.2*, 61.8, 61.7*, 61.5
of cis/trans isomer of 4g (82% yield, cis/trans¼10:90).
4.2.14. Cyclisation of a mixture of 3j and 4j to g-lactam
4j. According to the general procedure as described for com-
pound 4a, a solution of 1 (0.316 g, 1 mmol) in THF (2 mL)
and imine 2j (0.211 g, 1 mmol) were employed, after aque-
ous work-up, to yield the crude material. Without chromato-
graphic purification, the crude product was treated with
K CO (0.138 g, 1 mmol) in dry EtOH (20 mL) and the mix-
(
major- and minor-isomer), 59.4*, 59.2, 56.53*, 56.5,
4
(
8.8*, 48.7, 35.2*, 32.8, 14.74, 14.7*. IR (neat): nmax 3395
N–H), 1732 (C]O of ester) cm . MS: m/z (%) relative in-
ꢂ1
+
+
tensity 416 ([M+1] , 7), 415 ([M] , 2), 242 (100), 104 (32),
1 (1), 77 (10). HRMS (ESI-TOF) calcd for C H NO
6
9
2
5
30
+
[
M+1] : 416.2073; found: 416.2070.
2
3
ture was refluxed for 4 h under an argon atmosphere. After
the mixture was cooled to room temperature, the reaction
mixture was quenched with 1 M HCl, and EtOH was re-
moved (aspirator). The residue was extracted with EtOAc
(3ꢁ20 mL). The combined organic layers were washed
with water and brine, and dried over anhydrous Na SO . Af-
4
1
.2.12. Preparation of ethyl 2-(4-methoxyphenyl)-5-oxo-
-phenylpyrrolidine-3-carboxylate (4l). According to the
general procedure as described for compound 4a, a solution
of 1 (0.318 g, 1 mmol) in THF (2 mL) was treated with
imine 2l (0.211 g, 1 mmol) under an argon atmosphere. A
crude product 4l was purified by preparative thin-layer chro-
2
4
ter removal of solvent under reduced pressure, a crude prod-
uct was purified by preparative thin-layer chromatography
(SiO , 20% EtOAc in hexanes, triple runs) to give a mixture
matography (SiO , 20% EtOAc in hexanes, triple runs) to
2
give a pure trans-isomer (0.210 g, 62% yield as a pale yellow
oil) and cis-isomer (71 mg, 21% yield as a pale yellow oil) of
product 4l.
2
of cis/trans isomer of 4j (82% yield, cis/trans¼0:100).
4
.2.15. Cyclisation of a mixture of 3k and 4k to g-lactam
1
4
.2.12.1. trans-4l. H NMR (300 MHz, CDCl ): d 7.27
3
4k. According to the general procedure as described for
compound 4a, a solution of 1 (0.318 g, 1 mmol) in THF
(2 mL) and imine 2k (0.241 g, 1 mmol) were employed, af-
ter aqueous work-up, to yield the crude material. Without
chromatographic purification, the crude product was treated
with K CO (0.138 g, 1 mmol) in dry EtOH (20 mL) and the
(
d, J¼7.8 Hz, 2H), 7.16 (t, J¼7.3 Hz, 2H), 7.08 (d,
J¼8.6 Hz, 2H), 6.99 (t, J¼7.3 Hz, 1H), 6.78 (d, J¼8.6 Hz,
2
3
H), 5.39 (d, J ¼4.9 Hz, 1H), 4.14 (q, J¼7.1 Hz, 2H),
trans
.66 (s, 3H), 2.75–3.10 (m, 3H), 1.19 (t, J¼7.1 Hz, 3H).
1
3
C NMR (75 MHz, CDCl ): d 172.2, 172.0, 159.3, 137.4,
3
2
3
1
4
1
3
31.5, 128.6, 127.4, 125.3, 122.9, 114.3, 65.4, 61.5, 55.1,
6.7, 34.4, 14.1. IR (neat): n 1732 (C]O of ester),
704 (C]O of amide) cm . MS: m/z (%) relative intensity
mixture was refluxed for 4 h under an argon atmosphere. Af-
ter the mixture was cooled to room temperature, the reaction
mixture was quenched with 1 M HCl, and EtOH was re-
moved (aspirator). The residue was extracted with EtOAc
(3ꢁ20 mL). The combined organic layers were washed
with water and brine, and dried over anhydrous Na SO . Af-
max
ꢂ1
+
+
40 ([M+1] , 24), 339 ([M] , 55), 210 (100), 91 (43), 77
+
(
65). HRMS (ESI-TOF) calcd for C H NO [M+1] :
20 22 4
3
40.1549; found: 340.1549.
2
4
ter removal of solvent under reduced pressure, a crude prod-
uct was purified by preparative thin-layer chromatography
(SiO , 20% EtOAc in hexanes, triple runs) to give a mixture
of cis/trans isomer of 4k (82% yield, cis/trans¼5:95).
1
4
.2.12.2. cis-4l. H NMR (300 MHz, CDCl ): d 7.35 (d,
3
J¼8.0 Hz, 2H), 7.15 (m, 2H), 7.05 (t, J¼8.7 Hz, 3H), 6.74
2
(
(
2
d, J¼8.7 Hz, 2H), 5.38 (d, J ¼8.8 Hz, 1H), 3.90–3.60
cis
m, 3H), 3.68 (s, 3H), 3.28 (dd, J¼17.5, 10.9 Hz, 1H),
1
3
.67 (dd, J¼17.5, 8.9 Hz, 1H), 0.97 (t, J¼7.1 Hz, 3H).
C
NMR (125 MHz, CDCl ): d 172.6, 169.6, 159.6, 137.8,
4.3. Isomerisation of cis-g-lactam 4 to trans-g-lactam 4
3
1
4
1
3
28.7, 128.2, 128.0, 125.2, 122.2, 113.9, 64.7, 61.0, 55.1,
3.7, 32.9, 13.8. IR (CHCl ): n
4.3.1. General procedure. To a solution of the mixture of
diastereomers of 4a (87.5 mg, 0.25 mmol) in THF (1 mL)
was added dropwise a THF solution of DBU (10 mg,
1732 (C]O of ester),
max
3
ꢂ1
697 (C]O of amide) cm . MS: m/z (%) relative intensity
40 ([M+1] , 20), 339 ([M] , 100), 266 (61), 210 (90), 91
+
+
ꢀ
0.063 mmol) at 0 C under an argon atmosphere. The reac-
(
[
16), 77 (22). HRMS (ESI-TOF) calcd for C H NO Na
2
M+Na] : 362.1368; found: 362.1368.
tion mixture was slowly warmed up to room temperature
and stirred for 2 days. It was quenched with 0.5 N HCl
0
21
4
+
(
0.5 mL) and extracted with EtOAc (3ꢁ20 mL). The com-
4
4
.2.13. Cyclisation of a mixture of 3g and 4g to g-lactam
g. According to the general procedure as described for
bined organic layers were washed with water and brine,
and dried over anhydrous Na SO . The crude product, which
2
4
compound 4a, a solution of 1 (0.320 g, 1 mmol) in THF
2 mL) and imine 2g (0.181 g, 1 mmol) were employed, af-
consisted of an 80:20 mixture of trans/cis diastereomer was
purified by preparative thin-layer chromatography SiO2,
20% EtOAc in hexanes) to give a yellow oil (70 mg, 80%
(
ter aqueous work-up, to yield the crude material. Without
chromatographic purification, the crude product was treated
with K CO (0.138 g, 1 mmol) in dry EtOH (20 mL) and the
1
yield, trans/cis¼80:20). H NMR (300 MHz, CDCl3,
cis-isomer marked as *): d 7.45–7.00 (m, 20H, ArH of trans-
and cis-isomer), 5.10* (d, J¼14.7 Hz, 1H), 5.09 (d, J¼
2
3
mixture was refluxed for 4 h under an argon atmosphere. Af-
ter the mixture was cooled to room temperature, the reaction
mixture was quenched with 1 M HCl, and EtOH was re-
moved (aspirator). The residue was extracted with EtOAc
14.7 Hz, 1H), 4.68* (d, J ¼9.3 Hz, 1H), 4.60 (d, J
cis
¼
trans
5.5 Hz, 1H), 4.08 (q, J¼7.1 Hz, 2H), 3.55–3.80* (m, 3H),
3.48 (d, J¼14.7 Hz, 1H), 3.42* (d, J¼14.7 Hz, 1H), 3.17*

4336
M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
(
3
dd, J¼17.3, 10.2 Hz, 1H) 2.60* (dd, J¼17.3, 9.3 Hz, 1H),
128.9*, 128.6, 128.44*, 128.45, 127.9*, 127.7, 63.0 (trans-
and cis-isomer), 61.5, 60.4*, 46.0, 45.7*, 44.5, 42.8*, 33.5,
.10–2.90 (m, 1H), 2.90–2.70 (m, 2H), 1.16 (t, J¼7.1 Hz,
3
1
3
3
cis-isomer marked as *): d 173.1*, 172.7, 172.0, 169.9*,
1
1
6
1
H), 0.87* (t, J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl ,
31.8*, 14.0, 13.7*. IR (CHCl ): n
3
1735 (C]O of ester),
max
ꢂ1
1686 (C]O of amide) cm . MS: m/z (%) relative intensity
+
+
38.8, 135.7*, 135.6*, 135.5, 129.1*, 129.0, 128.5*, 128.4,
28.3*, 128.2, 127.5*, 127.4, 126.8*, 126.7, 63.5, 62.1*,
1.2, 60.7*, 45.8, 44.4*, 44.3, 42.8*, 33.3, 31.7*, 13.9,
358 ([M+1] , 15), 357([M] , 10), 266 (100), 119 (15), 118
(25), 91 (43), 77 (5), 65 (11). HRMS (ESI-TOF) calcd for
C H NO ClNa [M+Na] : 380.1022; found: 380.1029.
+
2
0
20
3
3.5*. IR (CHCl ): n
3
1731 (C]O of ester), 1682 (C]O
max
ꢂ1
of amide) cm . MS: m/z (%) relative intensity 324
(
4.3.4. Isomerisation of g-lactam 4d. According to the gen-
eral procedure, a solution of 4d (0.190 g, 0.5 mmol) in THF
(1 mL) was reacted with a THF solution of DBU (20 mg,
0.13 mmol) to give a crude product, which consisted of an
80:20 mixture of trans/cis isomer of 4d. Purification by pre-
+
+
[M+1] , 3), 323 ([M] , 9), 232 (100), 146 (10), 145 (8),
19 (9), 118 (18), 91 (31), 77 (5), 65 (7). HRMS (ESI-
TOF) calcd for C H NO Na [M+Na] : 346.1411; found:
1
+
2
0
21
3
3
46.1419.
parative thin-layer chromatography (SiO , 20% EtOAc in
2
4
.3.2. Isomerisation of g-lactam 4b. According to the gen-
hexanes) afforded a pale yellow oil of 4d (0.114 g, 60% yield,
1
eral procedure, a solution of 4b (0.1765 g, 0.5 mmol) in THF
1 mL) was reacted with a THF solution of DBU (20 mg,
trans/cis¼80:20). g-Lactam 4d: H NMR (300 MHz, CDCl ,
3
(
cis-isomer marked as *): d 8.17 (d, J¼8.7 Hz, 4H, ArH of
trans- and cis-isomer), 7.27 (d, J¼8.7 Hz, 4H, ArH of trans-
and cis-isomer), 7.15–7.35 (m, 6H, ArH of trans- and cis-iso-
mer), 6.95–6.85 (m, 4H, ArH of trans- and cis-isomer), 5.16*
(d, J¼14.7 Hz, 1H), 5.05 (d, J¼14.7 Hz, 1H), 4.71* (d,
J ¼9.4 Hz, 1H), 4.64 (d, J ¼5.8 Hz, 1H), 4.05 (q,
0.12 mmol) to give an 85:15 mixture of trans/cis isomer of
4b. It was purified by thin-layer chromatography (SiO2,
20% EtOAc in hexanes) to afford a pale yellow oil of 4b
1
(
(
(
0.1498 g, 85% yield, trans/cis¼85:15).
H
300 MHz, CDCl , cis-isomer marked as *): d 7.29–7.10
NMR
3
cis
trans
m, 6H, ArH of trans- and cis-isomer), 7.10–6.89 (m, 8H,
J¼7.1 Hz, 2H), 3.40–3.85* (m, 3H), 3.45 (d, J¼14.7 Hz,
2H, NCHHAr of trans- and cis-isomer), 3.10* (dd, J¼17.4,
10.2 Hz, 1H), 2.61* (dd, J¼17.4, 9.4 Hz, 1H), 3.00–2.85
(m, 1H), 2.85–2.60 (m, 2H), 1.11 (d, J¼7.1 Hz, 3H), 0.86*
ArH of trans- and cis-isomer), 6.89–6.71 (m, 4H, ArH of
trans- and cis-isomer), 5.06* (d, J¼14.7 Hz, 1H), 4.99 (d,
J¼14.7 Hz, 1H), 4.57* (d, J ¼9.3 Hz, 1H), 4.48 (d,
cis
1
3
J
¼5.8 Hz, 1H), 4.00 (q, J¼7.1 Hz, 2H), 3.80–3.48*
(t, J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl ) of the major
trans
3
(
m, 3H), 3.75 (s, 3H), 3.73* (s, 3H), 3.40 (d, J¼14.7 Hz,
trans-isomer: d 172.7, 171.3, 148.0, 146.4, 134.9, 128.7,
128.3, 127.9, 127.86, 124.3, 62.8, 61.7, 45.8, 44.8, 33.2,
2
1
2
0
H, NCHHAr of trans- and cis-isomer), 3.05–2.85 (m,
H), 2.85–2.65 (m, 2H), 3.12* (dd, J¼17.3, 10.3 Hz, 1H),
.54* (dd, J¼17.3, 9.3 Hz, 1H), 1.09 (t, J¼7.1 Hz, 3H),
14.0. IR (neat): n
amide) cm . MS: m/z (%) relative intensity 369 ([M+1] ,
1733 (C]O of ester), 1691 (C]O of
max
ꢂ1
+
+
1
3
.85* (t, J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl , cis-
3), 368 ([M] , 11), 274 (100), 119 (8), 118 (19), 91 (41), 77
(5), 65 (9). HRMS (ESI-TOF) calcd for C H N O Na
[M+Na] : 391.1270; found: 391.1269.
3
isomer marked as *): d 174.8*, 172.9 (trans- and cis-isomer),
72.2, 159.7 (trans- and cis-isomer), 135.5 (trans- and cis-
isomer), 130.6 (trans- and cis-isomer), 128.7*, 128.5,
2
0 20 2 5
+
1
1
1
4
1
28.44*, 128.4, 128.3*, 128.2, 127.7, 127.3*, 114.4,
14.0*, 63.3, 63.2*, 61.8*, 61.3, 55.3, 55.26*, 46.2, 45.9*,
4.4*, 44.3, 33.7, 31.9*, 14.0, 13.7*. IR (CHCl ): n
4.3.5. Isomerisation of g-lactam 4f. According to the gen-
eral procedure, a solution of 4f (0.191 g, 0.5 mmol) in THF
(1 mL) was reacted with a THF solution of DBU (20 mg,
0.13 mmol) to give a crude product, which consisted of
a 90:10 mixture of trans/cis isomer of 4f. Purification by pre-
3
ꢂ1
max
735 (C]O of ester), 1683 (C]O of amide) cm . MS:
+
+
m/z (%) relative intensity 354 ([M+1] , 9), 353 ([M] , 18),
62 (100), 119 (23), 118 (25), 91 (84), 77 (10), 65 (13).
HRMS (ESI-TOF) calcd for C H NO Na [M+Na] :
2
parative thin-layer chromatography (SiO , 20% EtOAc in
2
hexanes) afforded a pale yellow oil of 4f (0.133 g, 70% yield,
+
2
1
24
4
1
3
76.1525; found: 376.1524.
trans/cis¼90:10). H NMR (300 MHz, CDCl , cis-isomer
3
marked as *): d 7.30–6.53 (m, 16H, ArH of trans- and cis-iso-
mer), 5.13* (d, J¼14.6 Hz, 1H), 5.04 (d, J¼14.6 Hz, 1H),
4.64* (d, J ¼9.3 Hz, 1H), 4.55 (d, J ¼6.0 Hz, 1H),
4
.3.3. Isomerisation of g-lactam 4c. According to the gen-
eral procedure, a solution of 4c (0.168 g, 0.46 mmol) in THF
1 mL) was reacted with a THF solution of DBU (18 mg,
.12 mmol) to give a crude product, which consisted of
cis
trans
(
0
4.10 (q, J¼7.1 Hz, 2H), 3.90–3.30* (m, 3H), 3.90 (s, 3H),
3.88* (s, 3H), 3.82 (s, 6H, OCH of trans- and cis-isomer),
3
a 90:10 mixture of trans/cis isomer of 4c. It was purified
by preparative thin-layer chromatography SiO , 20% EtOAc
3.56 (d, J¼14.6 Hz, 1H), 3.48* (d, J¼14.6 Hz, 1H), 3.21*
(d, J¼17.3, 10.1 Hz, 1H), 2.55*(dd, J¼17.3, 9.4 Hz, 1H),
13
2
in hexanes) to give a pale yellow oil of 4c (0.135 g, 80%
yield, trans/cis¼90:10). H NMR (300 MHz, CDCl , cis-
3.10–3.00 (m, 1H), 2.90–2.65 (m, 2H), 1.10 (d, J¼7.1 Hz,
1
3H), 0.84* (t, J¼7.1 Hz, 3H). C NMR (75 MHz, CDCl ,
3
3
isomer marked *): d 7.30–6.80 (m, 18H, ArH of trans- and
cis-isomer), 5.08* (d, J¼14.7 Hz, 1H), 5.02 (d,
cis-isomer marked as *): d 173.0*, 172.7, 172.2, 170.0*,
149.5, 149.2*, 149.1, 149.0*, 136.0*, 135.7, 131.1 (trans-
and cis-isomer), 128.6*, 128.5, 128.4 (trans- and cis-isomer),
128.0*, 127.7*, 120.2, 119.5*, 111.2, 110.9*, 110.4*, 109.5,
63.6, 62.1*, 61.3, 60.8*, 55.9, 55.8*, 46.2, 44.5, 44.47*,
J¼14.7 Hz, 1H), 4.58* (d, J ¼9.3 Hz, 1H), 4.50 (d,
cis
J
¼5.7 Hz, 1H), 4.03 (q, J¼7.1 Hz, 2H), 3.90–3.40*
trans
(
m, 3H), 3.45 (d, J¼14.7 Hz, 2H, NCHHAr of trans- and
cis-isomer), 2.56* (dd, J¼17.3, 9.40 Hz, 1H), 3.10* (dd,
J¼17.3, 10.2 Hz, 1H), 3.05–2.85 (m, 1H), 2.85–2.65 (m,
42.9*, 33.8, 32.0*, 14.0, 13.7*. IR (CHCl ): n
3
1730
max
ꢂ1
(C]O of ester), 1682 (C]O of amide) cm . MS: m/z (%)
1
3
+
+
2 C
NMR (75 MHz, CDCl , cis-isomer marked as *): d 174.1*,
H), 1.09 (t, J¼7.1 Hz, 3H), 0.83* (t, J¼7.1 Hz, 3H).
relative intensity 384 ([M+1] , 8), 383 ([M] , 34), 292
(100), 119 (11), 118 (17), 91 (56), 77 (6), 65 (12). HRMS
(ESI-TOF) calcd for C H NO Na [M+Na] : 406.1630;
3
+
173.0*, 172.9, 171.8, 137.5*, 137.4, 135.2 (trans- and cis-
isomer), 134.4 (trans- and cis-isomer), 129.3, 129.0*,
2
2
25
5
found: 406.1631.

M. Pohmakotr et al. / Tetrahedron 63 (2007) 4328–4337
4337
Acknowledgements
3462–3471; (c) DiMauro, E.; Fry, A. J. Tetrahedron Lett.
999, 40, 7945–7949.
1
We acknowledge generous financial supports from the
Higher Education Development Program: Postgraduate
Education and Research Program in Chemistry (PERCH)
and the Thailand Research Fund to M.P. (BRG 49800005)
and to V.R. (Senior Research Scholar).
7. Park, J.-H.; Ha, J.-R.; Oh, S.-J.; Kim, J.-A.; Shin, D.-S.; Won,
T.-J.; Lam, Y.-F.; Ahn, C. Tetrahedron Lett. 2005, 46, 1755–
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. (a) Pohmakotr, M.; Komutkul, T.; Tuchinda, P.; Prabpai, S.;
Kongsaeree, P.; Reutrakul, V. Tetrahedron 2005, 61, 5311–
References and notes
5
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1
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3
1
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2
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4
11. Some recent reactions of ketene silylated acetals, see: (a) Hart,
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Yanai, T.; Mukaiyama, T. Chem. Lett. 2005, 34, 216–217.
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were consistent with the reported values (Jcis is larger than
(
Chem. 1998, 63, 6546–6553; (c) Craig, D.; Hyland, C. J. T.;
Ward, S. E. Chem. Commun. 2005, 3439–3441; (d) Poli, G.;
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2
005, 7, 995–998.
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3189.
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2006, 12, 5082–5093.
14. Assignment of isomer was not carried out since the coupling
constants of each isomer are in the same degree.
5
6
. He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131–3134 and refer-
ences cited therein.
. (a) Abbas, M.; Neuhaus, C.; Krebs, B.; Westermann, B.
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