Facile stereoselective synthesis of (E)- and (Z)-α-substituted cinnamates: stereospecific dehydration reaction with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and copper(II) chloride

Article abstract of DOI:10.1016/j.tet.2007.07.069

A highly stereoselective method for the synthesis of (E)- and (Z)-α-substituted cinnamates in good yield has been achieved by?dehydration reaction of anti- and syn-α-substituted-β-hydroxyphenylpropiolate using EDC. This facile method has been used to synt

Full text of DOI:10.1016/j.tet.2007.07.069

Tetrahedron 63 (2007) 10345–10353
Facile stereoselective synthesis of (E)- and (Z)-a-substituted
cinnamates: stereospecific dehydration reaction with
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC) and copper(II) chloride
b
b
Hiroshi Sai,a, Tsuyoshi Ogiku and Hiroshi Ohmizu
*
aClinical Research Division, Tanabe Seiyaku Co., Ltd, 3-2-10 Dosho-machi, Chuo-ku, Osaka 541-8505, Japan
bMedicinal Chemistry Research Laboratories, Tanabe Seiyaku Co., Ltd, 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan
Received 11 June 2007; revised 12 July 2007; accepted 17 July 2007
Available online 27 July 2007
Abstract—A highly stereoselective method for the synthesis of (E)- and (Z)-a-substituted cinnamates in good yield has been achieved
by dehydration reaction of anti- and syn-a-substituted-b-hydroxyphenylpropiolate using EDC. This facile method has been used to syn-
thesize various (E)- and (Z)-a-substituted cinnamates and (E)- and (Z)-a-alkylidene-g-butyrolactones. The reaction mechanism of this highly
stereospecific dehydration using EDC can be elucidated by the u-dimethylamino group of EDC, which is believed to facilitate the deproto-
nation step.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
However, preparation of (Z)-a-substituted cinnamates from
the corresponding anti-b-hydroxyesters was not stereosel-
ective (vide infra).3 This is probably due to the fact that
a-proton of the b-hydroxyester is too acidic for E2 elimina-
tion reaction to compete with E1cB elimination reaction.4
Therefore, the thermodynamically stable (E)-a-substituted
cinnamates were obtained predominantly. Similar results
have been reported in the synthesis of a-benzylidene-g-
butyrolactones5 and a-benzylideneketones.6 In order to solve
this problem, three methods based on Honer–Emmons reac-
tion,7 Baylis–Hillman reaction,8 and the reductive elimina-
tion reaction of syn-b-hydroxy-a-phenylthioester9 have
been reported. However, these methods have disadvantages,
such as the use of expensive and not easily accessible
reagents, and limitation of substituents at the a-position.
Meanwhile, Corey and Letavic have reported that (E)- and
(Z)-a-alkylidene-g-butyrolactones can stereoselectively be
synthesized by dehydration reaction of the corresponding
anti- and syn-a-(10-hydroxyalkyl)-g-butyrolactones with
N,N0-dicyclohexylcarbodiimide (DCC) and CuCl2.10 In
this case the isourea-mediated six membered cycloelimi-
nation reaction proceeds stereoselectively to provide the
(E)- and (Z)-a-substituted cinnamates from the anti- and
syn-a-substituted-b-hydroxyphenylpropionates, respectively.
Recently, we have reported a facile method for the stereo-
selective synthesis of (E)- and (Z)-a-substituted cinna-
mates based on stereoselective dehydration of the easily
accessible anti- and syn-a-substituted-b-hydroxyphenylpro-
pionatesby1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
Trisubstituted olefins represent an important class of com-
pounds since they are found in a wide variety of natural prod-
ucts and serve as valuable building blocks for the synthesis
of various types of natural products and biologically impor-
tant substances.1 Highly stereoselective construction of tri-
substituted olefins is one of the most challenging problems
in synthetic organic chemistry.2 Since trisubstituted olefins
bearing an electron-withdrawing group of E geometry are
thermodynamically more stable than their Z counterparts,
they are rather easy to come by. However, the methods avail-
able for moderate to highly stereoselective preparation of
(Z)-trisubstituted olefins are rather limited.
In the course of our synthetic studies and extensive search
for biologically active compounds, we needed a facile
stereoselective method for the synthesis of (E)- and (Z)-a-
substituted cinnamates. The simplest method we could
hit upon was E2 elimination reaction of the corresponding
syn- and anti-b-hydroxyesters. Indeed, stereoselective
(E)-a-substituted cinnamates were obtained in high yield
from the corresponding syn-b-hydroxyesters by E2 elimina-
tion reaction.
Keywords: a-Substituted cinnamates; a-Alkylidene-g-butyrolactones; Ste-
reospecific dehydration; syn-Elimination; Carbodiimide.
* Corresponding author. Tel.: +81 6 6205 5528; fax: +81 6 6205 5241;
e-mail: h-sai@tanabe.co.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.069

10346
H. Sai et al. / Tetrahedron 63 (2007) 10345–10353
(EDC) (Scheme 1).11 Herein we describe in detail our study
on the highly stereospecific dehydration of (E)- and (Z)-a-
substituted cinnamates using EDC and the possible reaction
mechanism.
(Entry 5). Next, we considered that the desired (Z)-cinna-
mate Z-2 can selectively be obtained using an appropriate
carbodiimide that promotes the elimination reaction to pro-
ceed sufficiently faster than the isomerization reaction.
Thus, we examined the sterically less hindering N,N0-diiso-
propylcarbodiimide (DIPC) and EDC. Indeed, DIPC im-
proved both the ratio and yield of Z-2, however, this
improvement was unsatisfactory (Entry 6). On the other
hand, dehydration reaction of anti-1 and syn-1 with EDC
was highly stereospecific giving E-2 and Z-2, respectively,
in high yields (Entries 7 and 8).
OH
EDC (2eq)
CuCl2 (0.1eq)
toluene, 80 °C
MeO
MeO
CO2Me
OTBS
MeO
MeO
CO2Me
OTBS
anti
OH
E
EDC (2eq)
MeO
MeO
OTBS
MeO
MeO
CO2Me
OTBS
CuCl2 (0.1eq)
With these promising results in hand, we next examined the
optimal reaction conditions. The reaction was first examined
in toluene at 25, 50, and 100 ꢀC (Table 2). At the low temper-
atures (25 and 50 ꢀC) the reaction needed rather a long pe-
riod of time to complete, and both the yield and selectivity
were lower than those at 80 ꢀC (Entries 2 and 3). Almost
the same yield and selectivity as those obtained at 80 ꢀC
were observed when the reaction was carried out at 100 ꢀC
(Entry 4).
CO2Me
toluene, 80 °C
syn
Z
Scheme 1. Stereospecific dehydration reaction with EDC and CuCl2.
2. Results and discussion
Detail of dehydration reaction of the anti- and syn-b-hydroxy-
esters 1 with carbodiimides under different conditions are
summarized in Table 1. Dehydration reaction of the anti-
b-hydroxyester anti-1 with DCC in Et2O at 35 ꢀC selectively
gave the (E)-cinnamate E-2 (Entry 1). This reaction pro-
ceeded more easily in toluene at 80 ꢀC (Entry 3). However,
dehydration reaction of the syn-b-hydroxyester syn-1 with
DCC in Et2O at 35 ꢀC did not proceed, instead, isomeri-
zation of syn-1 took place (Entry 2). The inversion reaction
of secondary alcohol for DCC and CuCl was reported.12 In
toluene at 80 ꢀC, dehydration reaction of syn-1 provided
a 2:1 mixture of the E- and Z-cinnamates in 45% yield al-
though the Z-cinnamate had been expected to be the major
product if the reaction proceeded in a stereospecific fashion
(Entry 4). Because the (Z)-isomer obtained did not isomerize
to the (E)-isomer under our reaction conditions,13 we consid-
ered that isomerization of syn-1 into anti-1 took place before
dehydration reaction leading to a mixture of the correspond-
ing cinnamates. In order to avoid isomerization by trapping
the liberated water molecule from 1, we added the molecular
sieve 4A into the reaction system. Although the effect of this
addition was small, the ratio and yield of Z-2 were improved
The reaction was also examined with various solvents at
80 ꢀC or under refluxing conditions (Table 3). In all cases,
Table 2. Effect of temperature on dehydration reaction of syn-1 with EDC
and CuCl2
OH
EDC (2eq)
CuCl2 (0.1eq)
toluene
MeO
MeO
CO2Me
OTBS
MeO
MeO
OTBS
CO2Me
syn-1
Z-2
Entry Solvent Temperature (ꢀC) Time (h) Yielda (%) Z:Eb
1
2
3
4
Toluene
Toluene
Toluene
80
25
50
2
96
16
2
95
45
69
94
96:4
88:12
92:8
95:5
Toluene 100
a
Combined isolated yields of (Z)- and (E)-cinnamates.
Determined by 1H NMR measurement of the crude mixture.
b
Table 3. Effect of solvent on dehydration reaction of syn-1 with EDC and
CuCl2
Table 1. Dehydration reaction of 1 with carbodiimide and CuCl2
OH
OH
EDC (2eq)
CuCl2 (0.1eq)
Solvent
MeO
MeO
CO2Me
OTBS
MeO
MeO
OTBS
Carbodiimide (2eq)
CuCl2 (0.1eq)
Solvent
MeO
MeO
CO2Me
OTBS
MeO
MeO
CO2Me
OTBS
CO2Me
syn-1
Z-2
syn-1 or anti-1
Z-2 or E-2
Entry Solvent
Temperature (ꢀC) Time (h) Yielda (%) Z:Eb
Entry Substrate Carbodiimide Solvent Temperature Time Yielda Z:Eb
1
2
Toluene 80
(CH2Cl)2 80
2
2
30
2
24
2
4
30
2
2
2
2
95
67
50
46
31
46
22
21
38
31
8
96:4
(ꢀC)
(h) (%)
70:30
78:22
85:15
95:5
81:19
66:34
86:14
85:15
75:25
70:30
71:29
1
2
3
4
5d
6
7
8
anti-1
syn-1
anti-1
syn-1
syn-1
syn-1
anti-1
syn-1
DCC
DCC
DCC
DCC
DCC
DIPC
EDC
EDC
Et2O
Et2O
35
35
24 52
1:>99
3
4
5
CH2Cl2
AcOEt
40
80
24 N.D.c
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
2
2
2
2
2
2
73
45
63
41
95
95
1:>99
33:67
47:53
44:56
1:>99
96:4
tBuOMe 55
6
7
8
THF
iPr2O
Et2O
65
70
35
9
Dioxane 80
10
11
12
DME
DMF
CH3CN
80
80
80
a
b
c
d
Combined isolated yield of (Z)- and (E)-cinnamates.
Determined by 1H NMR measurement of the crude mixture.
anti-1 was isolated in 23% yield and syn-1 was recovered in 30% yield.
57
a
Combined isolated yields of (Z)- and (E)-cinnamates.
Determined by 1H NMR measurement of the crude mixture.
b
Moleculer sieve 4A was used as an additive.

H. Sai et al. / Tetrahedron 63 (2007) 10345–10353
Table 4. Stereoselective synthesis of cinnamate with EDC and CuCl2
10347
Entry
Substrate
Carbodiimide
Product
Yielda (%)
Z:Eb
HO
OTBS
CO2Me
1
2
3
EDC
EDC (100 ꢀC)
DCC
60
99
32
86:14
>99:1
25:75
CO2Me
OTBS
4a
3a
HO
CO2Me
CO2Me
OTBS
4
EDC
99
1:>99
OTBS
4b
3b
HO
MeO
MeO
5
6
7
EDC
EDC (100 ꢀC)
DCC
52
72
24
75:25
79:21
20:80
MeO
MeO
CO2Me
CO2Me
CO2Me
6a
5a
HO
MeO
MeO
MeO
CO2Me
CO2Me
8
EDC
80
1:>99
MeO
6b
5b
HO
Cl
Cl
9
10
11
EDC
EDC (100 ꢀC)
DCC
50
96
20
86:14
95:5
22:78
Cl
Cl
CO2Me
CO2Me
8a
7a
HO
Cl
Cl
Cl
Cl
CO2Me
12
EDC
96
1:>99
8b
7b
HO
OTBS
13
14
15
EDC
EDC (100 ꢀC)
EDC (100 ꢀC, 24 h)
N.D.
4
18
CO2Me
>99:1
>99:1
CO2Me
OTBS
10a
9a
16
17
18
EDC
EDC (100 ꢀC)
EDC (100 ꢀC, 24 h)
N.D.
7
38
HO
1:>99
1:>99
CO2Me
OTBS
CO2Me
OTBS
10b
9b
Unless otherwise noted, reactions were carried out using carbodiimide (2 equiv) and CuCl2 (0.1 equiv) in toluene at 80 ꢀC for 2 h.
Combined isolated yields of (Z)- and (E)-cinnamates.
a
Determined by 1H NMR measurement of the crude mixture.
b
Z-2 was obtained predominantly. However, the new solvents
only brought about results inferior to those obtained with
toluene in terms of yield and stereoselectivity. Reactions
at lower temperature were sluggish (Entries 3, 5, and 8).
Thus, it was concluded that the reaction proceeds better in
toluene at a temperature over 80 ꢀC.
were obtained at 80 ꢀC, the yield and stereoselectivity
were improved at 100 ꢀC (Entries 2, 6, and 10). Tetrasubsti-
tuted alkenes were obtained with excellent stereoselectivity
in spite of low yield (Entries 13–18).
Dehydration reactions in a variety of a-substituted lactones
using EDC and DCC are shown in Table 5. With EDC,
(E)- and (Z)-a-benzylidene-g-butyrolactones and a-alkyl-
idene-g-butyrolactones were obtained stereoselectively in
moderate to good yields. In all cases, EDC was superior to
DCC. When comparing the products, the alkylidenes were
obtained in low yield but with high selectivity (Entries 8
and 10). The b-substituted lactones 18a and 18b were
obtained stereospecifically from the corresponding hydroxy-
lactones 17a and 17b (Entries 11 and 12).
In order to clarify the scope and limitations of the present
method, a variety of anti- and syn-a-substituted-b-hydroxy-
phenylpropionates were treated with EDC and DCC under
various reaction conditions (Table 4). With EDC, the reac-
tion stereoselectively proceeded to give the corresponding
(E)- and (Z)-a-substituted cinnamates in moderate to good
yields. In all cases, EDC was superior to DCC. The selectiv-
ity and yield decreased in the case of hydroxyester having
a methyl group at a-position (Entries 5 and 9), indicating
that a more sterically hindered substituent would be favor-
able for high selectivity. In the case where no good results
Based on these results, we considered the mechanism of the
reaction. It has been assumed that dehydration reaction using

10348
H. Sai et al. / Tetrahedron 63 (2007) 10345–10353
Table 5. Stereoselective synthesis of alkylidene-g-butyrolactone with EDC and CuCl2
Entry
Substrate
Carbodiimide
Product
Yielda (%)
Z:Eb
MeO
HO
MeO
O
O
H
MeO
MeO
1
2
EDC
DCC
78
55
80:20
32:68
O
O
O
11a
O
12a
HO
O
H
O
MeO
MeO
MeO
3
EDC
96
1:>99
O
MeO
12b
11b
HO
H
O
4
5
EDC
DCC
62
49
94:6
22:78
O
O
13a
14a
HO
H
O
O
6
EDC
62
1:>99
O
O
14b
13b
HO
O
H
H
O
7
8
9
EDC
EDC (100 ꢀC)
DCC
31
42
53
85:15
94:6
>99:1
O
O
16a
15a
HO
O
O
10
EDC
EDC
89
1:>99
O
O
16b
15b
HO
O
MeO
H
MeO
MeO
MeO
MeO
O
O
H
11
98
78:22
MeO
MeO
O
MeO
OMe
OMe
18a
17a
HO
O
O
O
H
H
MeO
MeO
MeO
MeO
O
12
EDC
99
1:>99
MeO
OMe
MeO
OMe
OMe
OMe
18b
17b
Unless otherwise noted, reactions were carried out using carbodiimide (2 equiv) and CuCl2 (0.1 equiv) in toluene at 80 ꢀC for 2 h.
Combined isolated yields of (Z)- and (E)-g-butyrolactones.
a
Determined by 1H NMR measurement of the crude mixture.
b
DCC proceeds via a six membered cycloelimination of
isourea (Scheme 2).14 In the case of our reaction, the
b-hydroxyesters anti-1 and syn-1 would condense with
DCC in the presence of CuCl2 to generate the isourea inter-
mediates 19a and 19b, respectively.15 The six membered
cycloelimination reaction of 19a would easily proceed to
afford the E-2. On the other hand, the six membered cyclo-
elimination reaction of 19b would hardly proceed at 35 ꢀC,
therefore syn-1 would not afford Z-2. As a result, substitu-
tion reaction of the hydroxyl group at the benzylic position12
occurs and a mixture of anti-1 and syn-1 is obtained. At
80 ꢀC, a mixture of E-2 and Z-2 is obtained because cyclo-
elimination reaction of 19b proceeds along that of 19a,
which is derived from the isomerized anti-1. The transition
structure (A) from the intermediate 19a and the transition
structures (B) and (C) from the intermediate 19b are shown
in Figure 1. The producing p–p orbital could be conjugated
with the aromatic p–p orbital and the carbonyl p–p orbital
in the transition structure (A) because the aromatic group
and the methoxycarbonyl group could be on the same plane

H. Sai et al. / Tetrahedron 63 (2007) 10345–10353
10349
HN
H
HN
R
DCC
OH
O
N
CuCl2
CO2Me
O
N
CO2Me
Ar
Ar
Ar
O
Ar
CO2Me
R
Ar
H2O
R
CO2Me
R
H
anti-1
19a
E-2
HN
H
HN
MeO2C
O
DCC
CuCl2
OH
N
R
CO2Me
O
N
Ar
CO2Me
Ar
CO2Me
Ar
H2O
R
R
H
R
syn-1
19b
Z-2
Scheme 2. Proposed reaction mechanism of dehydration reaction using DCC.
O
MeO
HN
HN
H
HN
R
O
N
N
O
N
H
H
OMe
R
MeO
O
O
H
H
(C)
H
R
(A)
(B)
E-2
Z-2
Z-2
Figure 1. Postulated transition structure from intermediate 19a and 19b.
in chair conformation. On the other hand, the transition
structures (B) and (C) could neither be in the same plane
nor in chair conformation. Therefore, elimination reaction
via (A) proceeds more easily than via (B) and (C) because
energy level of (A) is sufficiently low, while that of (B)
and (C) is high.
possesses an intramolecular basic dimethylamino group. In
order to clarify the role of this dimethylamino group in the
high efficiency of EDC, we examined the dehydration reac-
tion with DCC in the presence of triethylamine. The product
obtained was a mixture of E-2 and Z-2, but the selectivity
was slightly improved (Entries 1 and 2). Deprotonation
from the intermediate (19b) might have proceeded easily
in the presence of triethylamine. Next, we examined dehy-
dration with EDC$HCl, which lacks deprotonation ability.
Since EDC$HCl did not dissolve in toluene, the reaction
was performed in dichloroethane. EDC$HCl did not give
better selectivity than EDC (Entries 3 and 4). This finding
was as expected similar to the case of DCC. Although basic
reaction conditions can facilitate the deprotonation step,
DCC in the presence of triethylamine was not as effective
as EDC. Therefore, it was concluded that the dimethylamino
group plays an important role in the intramolecular deproto-
nation step.
As dehydration reaction of anti-1 and syn-1 with EDC gave
E-2 and Z-2 stereospecifically in high yields, we examined
the high efficiency of EDC (Table 6). Unlike DCC, EDC
Table 6. Dehydration reaction of syn-1 with carbodiimide and CuCl2
HO
Carbodiimide (2eq)
CuCl2 (0.1eq)
MeO
MeO
OTBS
MeO
MeO
CO2Me
OTBS
CO2Me
Z-2
syn-1
Entry Carbodiimide Solvent
Temperature Time Yielda Z:Eb
(ꢀC)
(h)
(%)
In order to examine the effect of carbon chain length, we
examined the dehydration reaction of syn-1 with 1-ethyl-
3-(2-dimethylaminoethyl)carbodiimide (20)16 shortened by
one carbon and 1-ethyl-3-(4-dimethylaminobutyl)carbo-
diimide (21) lengthened by one carbon, prepared from
N,N-dimethyl-1,4-butanediamine and ethyl isothiocyanate
according to a reported method.17 The reaction with 20
proceeded more slowly than that with EDC and the selec-
tively slightly was lowered (Entries 6 and 7). Almost the
same phenomena were observed in the reaction with 21
(Entries 8 and 9). As shown in Table 6, the dimethylamino-
propyl group afforded the best result in yield and selectivity.
1
2
3
4
5
6
7
8
9
DCC Toluene
DCC (+Et3N) Toluene
80
80
2
2
2
40
2
2
8
2
8
45
37
67
17
95
42
91
43
87
33:67
60:40
70:30
15:85
96:4
82:18
81:19
88:12
89:11
EDC
EDC$HCl
EDC
(20)
(CH2Cl)2c 80
(CH2Cl)2 80
Toluene
Toluene
Toluene
Toluene
Toluene
80
80
80
80
80
(20)
(21)
(21)
a
b
c
Combined isolated yields of (Z)- and (E)-cinnamates.
Determined by 1H NMR measurement of the crude mixture.
(CH2Cl)2 was used since EDC$HCl did not dissolve in toluene.

10350
H. Sai et al. / Tetrahedron 63 (2007) 10345–10353
NHEt
N
R
NHEt
N
NMe2
EDC
O
OH
Ar
CuCl2
CO2Me
O
:N
Me2
CO2Me
Ar
H
Ar
CO2Me
R
Ar
H2O
CO2Me
R
H
R
anti-1
22a
E-2
NHEt
N
MeO2C
O
NHEt
N
NMe2
EDC
CuCl2
OH
Ar
R
CO2Me
O
:N
Me2
CO2Me
Ar
H
Ar
CO2Me
Ar
H2O
R
H
R
R
syn-1
22b
Z-2
Scheme 3. Proposed reaction mechanism of dehydration reaction using EDC.
From these results, the reaction mechanism can be eluci-
dated as illustrated in Scheme 3. The u-dimethylamino
group in EDC does not only play the role of a base that
facilitates the deprotonation step, but also participates in
the six membered cycloelimination reaction to produce the
[6,6]-bicyclic intermediate in 22a and 22b. The [6,6]-
bicyclic intermediate shows strong deprotonation ability be-
cause energy level of the transition state is lowered to allow
elimination reaction to proceed easily owing to the effective
assistance by the intramolecular u-dimethylamino group.
Therefore, dehydration reaction with EDC can proceed
considerably faster than that with DCC and another carbodi-
imide. As a result, the anti- and syn-b-hydroxyesters anti-1
and syn-1 could give the (E)- and (Z)-cinnamates E-2 and
Z-2 stereospecifically in high yields.
carried out on E. Merck 0.25-mm precoated glass-backed
plates (60 F254). All solvents were dried by standard
methods, and all reactions were carried out under an inert
atmosphere.
4.1.1. Typical procedure for the dehydration reaction. A
solution of b-hydroxyester (0.25 mmol) in toluene (10 mL)
was treated with EDC (0.5 mmol) and CuCl2
(0.025 mmol) at 80 ꢀC for 2 h. The reaction mixture was
quenched with water and the mixture was extracted with
EtOAc. The organic layer was washed with aqueous citric
acid, aqueous NaHCO3, and brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed
on silica gel. Elution with hexane–AcOEt gave the product.
1
The E/Z ratio was determined by H NMR. When it was
necessary, the isomers were separated by preparative TLC
for characterization.
3. Conclusion
4.1.1.1. (Z)-4-(tert-Butyldimethylsilanyloxy)-2-(3,4-di-
methoxybenzylidene)-butyric acid methyl ester (Z-2).
Colorless oil. IR (film): 2955, 2850, 1705, 1600, 1515,
In summary, a highly stereoselective method for the syn-
thesis of (E)- and (Z)-a-substituted cinnamates and (E)-
and (Z)-a-alkylidene-g-butyrolactones was developed. It is
noteworthy that the (Z)-a-substituted cinnamates and the
(Z)-a-alkylidene-g-butyrolactones, which had hitherto
been difficult to obtain, could be stereoselectively synthe-
sized in good yields. The mechanism of this highly stereo-
specific dehydration reaction using EDC can be elucidated
by the u-dimethylamino group of EDC, which not only
plays a role in facilitating the deprotonation step but also
participates in the formation of [6,6]-bicyclic intermediate
in the six membered cycloelimination reaction.
1260, 1115, 835, 775 cmꢁ1 1H NMR (CDCl3) d: 0.05
.
(6H, s), 0.89 (9H, s), 2.60 (2H, t, J¼6.6 Hz), 3.67 (3H, s),
3.79 (2H, t, J¼6.6 Hz), 3.85 (s, 3H), 3.88 (3H, s), 6.67
(1H, s), 6.83 (3H, m). MS (EI): m/z 380 (M+), 349, 323
(100%), 291, 89. HRMS calcd for C20H32O5Si 380.2019,
found 380.2026.
4.1.1.2. (E)-4-(tert-Butyldimethylsilanyloxy)-2-(3,4-di-
methoxybenzylidene)-butyric acid methyl ester (E-2).
Colorless oil. IR (film): 2955, 2850, 1705, 1600, 1515,
1260, 1115, 835, 775 cmꢁ1. 1H NMR (CDCl3) d: 0.03 (6H,
s), 0.87 (9H, s), 2.85 (2H, t, J¼6.6 Hz), 3.81 (3H, s), 3.88
(2H, t, J¼6.6 Hz), 3.90 (3H, s), 3.92 (3H, s), 6.88 (1H, d,
J¼8.9 Hz), 7.16 (1H, s), 7.18 (1H, d, J¼8.9 Hz), 7.74 (1H,
s). MS (EI): m/z 380 (M+), 349, 323 (100%), 291, 89.
HRMS calcd for C20H32O5Si 380.2019, found 380.2024.
4. Experimental
4.1. General
€
Melting points were measured using a Buchi 535 capillary
melting point apparatus and are uncorrected. IR spectra
were recorded on a Perkin–Elmer 1640 infrared spectropho-
tometer. 1H spectra were recorded on a Bruker AC-200 spec-
trometer and a Bruker AVANCE 400 spectrometer with
tetramethylsilane used as an internal standard. Mass spectra
were recorded on a Hitachi M-2000A spectrometer. Silica
gel column chromatography was performed with Kieselgel
60 (E. Merck). Thin-layer chromatography (TLC) was
4.1.1.3. (Z)-2-Benzylidene-4-(tert-butyldimethylsila-
nyloxy)-butyric acid methyl ester (4a). Colorless oil. IR
1
(film): 2955, 1720, 1260, 1095, 835, 775, 700 cmꢁ1. H
NMR (CDCl3) d: 0.04 (6H, s), 0.88 (9H, s), 2.60 (2H, t,
J¼6.6 Hz), 3.61 (3H, s), 3.78 (2H, t, J¼6.6 Hz), 6.73 (1H,
s), 7.20 (5H, m). MS (SIMS): m/z 321 (M++H), 289, 263,
189, 89, 73 (100%). HRMS calcd for C18H29O3Si (M++H)
321.1887, found 321.1894.

H. Sai et al. / Tetrahedron 63 (2007) 10345–10353
10351
4.1.1.4. (E)-2-Benzylidene-4-(tert-butyldimethylsila-
nyloxy)-butyric acid methyl ester (4b). Colorless oil. IR
4.1.1.11. (Z)-3-(3,4-Dimethoxybenzylidene)-dihydro-
furan-2-one (12a). Colorless oil. IR (film): 2955, 2850,
1
1
(film): 2955, 1715, 1260, 1095, 835, 775, 705 cmꢁ1. H
1705, 1600, 1515, 1260, 1115, 835, 775 cmꢁ1. H NMR
NMR (CDCl3) d: 0.03 (6H, s), 0.87 (9H, s), 2.80 (2H, t,
J¼6.8 Hz), 3.81 (3H, s), 3.85 (2H, t, J¼6.8 Hz), 7.37 (3H,
m), 7.53 (2H, m), 7.79 (1H, s). MS (SIMS): m/z 321
(M++H), 289, 263, 189, 89, 73 (100%). HRMS calcd for
C18H29O3Si (M++H) 321.1887, found 321.1891.
(CDCl3) d: 3.13 (2H, dt, J¼2.2, 7.4 Hz), 3.92 (3H, s), 3.94
(3H, s), 4.40 (2H, t, J¼7.4 Hz), 6.84 (1H, d, J¼8.4 Hz),
6.90 (1H, t, J¼2.3 Hz), 7.22 (1H, dd, J¼8.4, 2.0 Hz), 8.13
(1H, d, J¼2.0 Hz). MS (EI): m/z 234(M+, 100%), 219.
HRMS calcd for C13H14O4 234.0892, found 234.0900.
4.1.1.5. (Z)-3-(3,4-Dimethoxyphenyl)-2-methylacrylic
acid methyl ester (6a). Colorless oil. IR (film): 2950,
1720, 1515, 1270, 1145, 1030, 765 cmꢁ1. 1H NMR (CDCl3)
d: 2.16 (3H, s), 3.69 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 6.63
(1H, s), 6.80 (1H, d, J¼8.2 Hz), 6.84 (1H, dd, J¼8.2,
2.0 Hz), 6.86 (1H, d, J¼2.0 Hz). MS (EI): m/z 236(M+,
100%), 221, 205, 176, 161. HRMS calcd for C13H16O4
236.1049, found 236.1053.
4.1.1.12. (E)-3-(3,4-Dimethoxybenzylidene)-dihydro-
furan-2-one (12b). Colorless prisms (ethyl acetate–hexane,
mp 135–136 ꢀC). IR (KBr): 2955, 2850, 1705, 1600, 1515,
1260, 1115, 835, 775 cmꢁ1. 1H NMR (CDCl3) d: 3.24 (2H,
dt, J¼2.8, 7.5 Hz), 3.92 (3H, s), 3.93 (3H, s), 4.47 (2H, t,
J¼7.5 Hz), 6.94 (1H, d, J¼8.4 Hz), 7.02 (1H, d, J¼1.9 Hz),
7.13 (1H, dd, J¼8.4, 1.9 Hz), 8.13 (1H, t, J¼2.8 Hz). MS
(EI): m/z 234 (M+, 100%), 219. Anal. calcd for C13H14O4:
C, 66.66; H, 6.02. Found: C, 66.61; H, 5.94.
4.1.1.6. (E)-3-(3,4-Dimethoxyphenyl)-2-methylacrylic
acid methyl ester (6b). Colorless oil. IR (film): 2955,
1705, 1515, 1250, 1115, 1025, 810 cmꢁ1. 1H NMR (CDCl3)
d: 2.16 (3H, s), 3.82 (3H, s), 3.90 (3H, s), 3.92 (3H, s), 6.90
(1H, d, J¼8.3 Hz), 6.95 (1H, d, J¼1.9 Hz), 7.04 (1H, dd,
J¼8.3, 1.9 Hz), 7.64 (1H, s). MS (EI): m/z 236(M+, 100%),
221, 205, 176, 161. HRMS calcd for C13H16O4 236.1049,
found 236.1052.
4.1.1.13. (Z)-3-But-2-enylidenedihydrofuran-2-one
(14a). Colorless oil. IR (film): 2915, 1745, 1650, 1195,
1
1145 cmꢁ1. H NMR (CDCl3) d: 1.88 (3H, t, J¼6.9 Hz),
2.96 (2H, t, J¼7.5 Hz), 4.34 (2H, t, J¼7.5 Hz), 6.01 (1H,
m), 6.58 (1H, dt, J¼11.3, 2.1 Hz), 7.44 (1H, m). MS (EI):
m/z 138 (M+, 100%), 123, 79. HRMS calcd for C8H10O2
138.0681, found 138.0687.
4.1.1.7. (Z)-3-(3,4-Dichlorophenyl)-2-methylacrylic
acid methyl ester (8a). Colorless oil. IR (film): 2950,
1725, 1470, 1225, 1125, 1030, 910 cmꢁ1. 1H NMR (CDCl3)
d: 2.09 (3H, s), 3.83 (3H, s), 7.21 (1H, dd, J¼8.1, 1.9 Hz),
7.46 (1H, d, J¼1.9 Hz), 7.47 (1H, d, J¼8.1 Hz), 7.56 (1H,
s). MS (EI): m/z 246(M+), 244(M+, 100%), 215, 213, 186,
184, 149, 115. HRMS calcd for C11H10Cl2O2 244.0058,
found 244.0063.
4.1.1.14. (E)-3-But-2-enylidenedihydrofuran-2-one
(14b). Colorless oil. IR (film): 2915, 1750, 1655, 1195,
1
1140 cmꢁ1. H NMR (CDCl3) d: 1.91 (3H, t, J¼5.2 Hz),
2.96 (2H, dt, J¼1.7, 7.6 Hz), 4.40 (2H, t, J¼7.6 Hz), 6.18
(1H, d, J¼9.2 Hz), 6.21 (1H, m), 7.08 (1H, dt, J¼9.2,
2.5 Hz). MS (EI): m/z 138 (M+, 100%), 123, 79. HRMS
calcd for C8H10O2 138.0681, found 138.0685.
4.1.1.15. (Z)-3-Isobutylidenedihydrofuran-2-one (16a).
4.1.1.8. (E)-3-(3,4-Dichlorophenyl)-2-methylacrylic
acid methyl ester (8b). Colorless oil. IR (film): 2955,
Colorless oil. IR (film): 2965, 1755, 1375, 1210, 1135 cmꢁ1
.
1H NMR (CDCl3) d: 1.02 (6H, d, J¼6.6 Hz), 2.90 (2H, dt,
J¼2.2, 7.4 Hz), 3.77 (1H, m), 4.31 (2H, t, J¼7.4 Hz), 6.02
(1H, dt, J¼10.0, 2.2 H). MS (EI): m/z 140 (M+, 100%), 125.
HRMS calcd for C8H12O2 140.0837, found 140.0845.
1
1715, 1475, 1250, 1115, 1030, 820, 750 cmꢁ1. H NMR
(CDCl3) d: 2.10 (3H, s), 3.67 (3H, s), 6.60 (1H, s), 7.06
(1H, dd, J¼8.3, 2.0 Hz), 7.33 (1H, d, J¼2.0 Hz), 7.36 (1H,
d, J¼8.3 Hz). MS (EI): m/z 246 (M+), 244 (M+, 100%),
215, 213, 186, 184, 149, 115. HRMS calcd for
C11H10Cl2O2 244.0058, found 244.0065.
4.1.1.16. (E)-3-Isobutylidenedihydrofuran-2-one
(16b). Colorless oil. IR (film): 2965, 1755, 1375, 1210,
1
1135 cmꢁ1. H NMR (CDCl3) d: 1.68 (6H, d, J¼6.7 Hz),
4.1.1.9. (Z)-2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-
3-phenylbut-2-enoic acid methyl ester (10a). Colorless
2.52 (1H, m), 2.89 (2H, dt, J¼3.3, 7.6 Hz), 4.38 (2H, t,
J¼7.6 Hz), 6.59 (1H, dt, J¼9.8, 2.9 Hz). MS (EI): m/z 140
(M+, 100%), 125. HRMS calcd for C8H12O2 140.0837,
found 140.0844.
oil. IR (film): 2955, 1715, 1250, 1105, 835, 775, 700 cmꢁ1
.
1H NMR (CDCl3) d: 0.07 (6H, s), 0.90 (9H, s), 2.14 (3H, s),
2.69 (2H, t, J¼7.0 Hz), 3.36 (3H, s), 3.76 (2H, t, J¼7.0 Hz),
7.12 (2H, m), 7.27 (3H, m). MS (EI): m/z 319 (M+ꢁCH3),
303, 287, 277 (100%), 245, 89. HRMS calcd for
C18H27O3Si (M+ꢁCH3) 319.1617, found 319.1624.
4.1.1.17. (Z)-3-(3,4-Dimethoxybenzylidene)-4-(3,4,5-
trimethoxybenzyl)-dihydrofuran-2-one (18a). Colorless
oil. IR (film): 2940, 2840, 1745, 1640, 1590, 1515, 1260,
1125, 775 cmꢁ1 1H NMR (CDCl3) d: 2.88 (2H, dd,
.
4.1.1.10. (E)-2-[2-(tert-Butyldimethylsilanyloxy)-
ethyl]-3-phenylbut-2-enoic acid methyl ester (10b). Col-
orless oil. IR (film): 2955, 1720, 1250, 1105, 835, 780,
J¼7.2, 5.1 Hz), 3.32 (1H, m), 3.81 (6H, s), 3.85 (3H, s),
3.91 (3H, s), 3.94 (3H, s), 4.14 (2H, m), 6.40 (2H, s), 6.53
(1H, d, J¼1.4 Hz), 6.83 (1H, d, J¼8.4 Hz), 7.15 (1H, dd,
J¼8.4, 2.0 Hz), 8.10 (1H, d, J¼2.0 Hz). MS (EI): m/z 414
(M+), 266, 233, 181 (100%). HRMS calcd for C23H26O7
414.1679, found 414.1689.
1
705 cmꢁ1. H NMR (CDCl3) d: 0.05 (6H, s), 0.87 (9H, s),
2.27 (3H, s), 2.45 (2H, t, J¼6.8 Hz), 3.60 (2H, t,
J¼6.8 Hz), 3.85 (3H, s), 7.21 (2H, m), 7.36 (3H, m). MS
(EI): m/z 319 (M+ꢁCH3), 303, 287, 277 (100%), 245, 89.
HRMS calcd for C18H27O3Si (M+ꢁCH3) 319.1617, found
319.1622.
4.1.1.18. (E)-3-(3,4-Dimethoxybenzylidene)-4-(3,4,5-
trimethoxybenzyl)-dihydrofuran-2-one (18b). Colorless

10352
H. Sai et al. / Tetrahedron 63 (2007) 10345–10353
prisms (ethyl acetate–hexane, mp 151–152 ꢀC). IR (KBr):
2940, 2840, 1745, 1645, 1590, 1515, 1250, 1125, 805 cmꢁ1
IR (film): 3515, 2950, 2840, 1735, 1595, 1515, 1460,
1265, 1140, 1030, 860, 810, 765 cmꢁ1. H NMR (CDCl3)
1
.
1H NMR (CDCl3) d: 2.65 (2H, dd, J¼14.4, 10.1 Hz), 3.09
(1H, dd, J¼14.4, 4.5 Hz), 3.81 (3H, s), 3.84 (6H, s), 3.91
(3H, s), 3.94 (3H, s), 4.30 (2H, m), 6.39 (2H, s), 6.92 (1H,
d, J¼8.4 Hz), 7.09 (1H, d, J¼2.0 Hz), 7.21 (1H, dd, J¼
8.4, 2.0 Hz), 7.55 (1H, d, J¼1.7 Hz). MS (EI): m/z 414 (M+),
233, 181 (100%). Anal. calcd for C23H26O7: C, 66.65; H,
6.32. found: C, 66.61; H, 6.14.
d: 1.15 (3H, d, J¼7.2 Hz), 2.78 (1H, dq, J¼4.4, 7.2 Hz), 3.68
(3H, s), 3.88 (3H, s), 3.89 (3H, s), 5.04 (1H, d, J¼4.4 Hz),
6.84 (1H, d, J¼8.0 Hz), 6.86 (1H, d, J¼8.0 Hz), 6.90 (1H,
s). MS (EI): m/z 254 (M+), 237, 167 (100%), 139. HRMS
calcd for C13H18O5 254.1154, found 254.1159.
4.1.2.6. Methyl (anti)-3-(3,4-dimethoxyphenyl)-3-hy-
droxy-2-methylpropionate (5b). Yield 35%. Colorless
oil. IR (film): 3505, 2940, 2840, 1735, 1595, 1515, 1460,
1265, 1140, 1025, 855, 820, 765 cmꢁ1. 1H NMR (CDCl3) d:
1.00 (3H, d, J¼8.2 Hz), 2.80 (1H, dq, J¼8.8, 8.2 Hz), 3.75
(3H, s), 3.88 (3H, s), 3.89 (3H, s), 4.70 (1H, d, J¼8.8 Hz),
6.84 (1H, d, J¼8.0 Hz), 6.86 (1H, d, J¼8.0 Hz), 6.91 (1H,
s). MS (EI): m/z 254 (M+), 237, 167 (100%), 139. HRMS
calcd for C13H18O5 254.1154, found 254.1160.
4.1.2. Typical procedure for substrate preparation. A so-
lution of ester or lactone (11.6 mmol) in dry THF (10 mL)
was treated with LDA solution (13.9 mmol) at ꢁ78 ꢀC under
N2 for 30 min. The reaction mixture was quenched with
aqueous NH4Cl and the mixture was extracted with EtOAc.
The organic layer was washed with aqueous citric acid,
aqueous NaHCO3, and brine, dried (MgSO4), and concen-
trated in vacuo. The mixture of anti-isomer and syn-isomer
was separated by column chromatography on silica gel.
4.1.2.7. Methyl (syn)-3-(3,4-dichlorophenyl)-3-hy-
droxy-2-methylpropionate (7a). Yield 50%. Colorless oil.
IR (film): 3485, 2990, 2955, 1730, 1565, 1460, 1350,
1205, 1030, 820, 740 cmꢁ1. 1H NMR (CDCl3) d: 1.09 (3H,
d, J¼7.2 Hz), 2.75 (1H, dq, J¼3.6, 7.2 Hz), 3.15 (1H, br s),
3.72 (3H, s), 5.09 (1H, d, J¼3.6 Hz), 7.17 (1H, dd, J¼8.2,
2.0 Hz), 7.41 (1H, d, J¼8.2 Hz), 7.47 (1H, d, J¼2.0 Hz).
MS (EI): m/z 264, 262 (M+), 247, 245, 177, 175, 88 (100%).
HRMS calcd for C11H12Cl2O3 262.0163, found 262.0159.
4.1.2.1. Methyl (syn)-3-(3,4-Dimethoxyphenyl)-3-hy-
droxy-2-[2-(tert-butyldimethylsilyloxy)-ethyl]-propionate
(syn-1). Yield 46%. Colorless oil. IR (film): 3515, 2955,
1
2860, 1735, 1595, 1515, 1260, 835, 775 cmꢁ1. H NMR
(CDCl3) d: 0.04 (6H, s), 0.88 (9H, s), 1.90 (2H, m), 2.60
(1H, dt, J¼2.8, 6.4 Hz), 3.53 (3H, s), 3.63 (2H, m), 3.83
(3H, s), 3.85 (3H, s), 4.90 (1H, d, J¼6.4 Hz), 6.78 (1H, d,
J¼8.2 Hz), 6.83 (1H, d, J¼8.2 Hz), 6.86 (1H, s). MS (EI):
m/z 398 (M+), 309, 232, 175 (100%), 166, 139, 89. HRMS
calcd for C20H34O6Si 398.2125, found 398.2136.
4.1.2.8. Methyl (anti)-3-(3,4-dichlorophenyl)-3-hy-
droxy-2-methylpropionate (7b). Yield 35%. Colorless nee-
dles (ethyl acetate–hexane, mp 96–97 ꢀC). IR (KBr): 3435,
2955, 1710, 1460, 1435, 1380, 1250, 1205, 1175, 1125,
1050, 875, 830 cmꢁ1. 1H NMR (CDCl3) d: 1.07 (3H, d, J¼
7.2 Hz), 2.76 (1H, dq, J¼8.0, 7.2 Hz), 3.73 (3H, s), 4.72 (1H,
d, J¼8.0 Hz), 7.17 (1H, dd, J¼8.2, 2.5 Hz), 7.43 (1H, d,
J¼8.2 Hz), 7.45 (1H, d, J¼2.5 Hz). MS (EI): m/z 264, 262
(M+), 247, 245, 177, 175, 88 (100%). Anal. calcd for
C11H12Cl2O3: C, 50.21; H, 4.60; Cl, 26.95. Found: C,
50.18; H, 4.44; Cl, 26.89.
4.1.2.2. Methyl (anti)-3-(3,4-Dimethoxyphenyl)-3-hy-
droxy-2-[2-(tert-butyldimethylsilyloxy)-ethyl]-propionate
(anti-1). Yield 46%. Colorless oil. IR (film): 3515, 2955,
1
2860, 1735, 1595, 1515, 1260, 835, 775 cmꢁ1. H NMR
(CDCl3) d: 0.02 (6H, s), 0.88 (9H, s), 1.59 (1H, m), 1.82
(1H, m), 2.64 (1H, br s), 2.96 (1H, m), 3.57 (2H, m), 3.71
(3H, s), 3.89 (6H, s), 4.78 (1H, d, J¼7.8 Hz), 6.84 (1H, d,
J¼8.2 Hz), 6.86 (1H, d, J¼8.2 Hz), 6.90 (1H, s). MS (EI):
m/z 398 (M+), 309, 232, 175 (100%), 166, 139, 89. HRMS
calcd for C20H34O6Si 398.2125, found 398.2132.
4.1.2.9. Methyl (syn)-3-hydroxy-3-phenyl-2-[2-(tert-
butyldimethylsilyloxy)-ethyl]-butyrate (9a). Yield 28%.
Colorless oil. IR (film): 3515, 2955, 2850, 1715, 1500,
4.1.2.3. Methyl (syn)-3-hydroxy-3-phenyl-2-[2-(tert-
butyldimethylsilyloxy)-ethyl]-propionate (3a). Yield
49%. Colorless oil. IR (film): 3500, 2955, 2850, 1735, 1255,
1100, 835, 775, 700 cmꢁ1. 1H NMR (CDCl3) d: 0.03 (6H, s),
0.85 (9H, s), 1.90 (2H, m), 2.85 (2H, dt, J¼5.9, 4.7 Hz), 3.54
(3H, s), 3.59 (2H, m), 4.98 (1H, d, J¼5.9 Hz), 7.30 (5H, m).
MS (EI): m/z 338 (M+), 307, 281, 249, 189, 175 (100%), 89.
HRMS calcd for C18H30O4Si 338.1913, found 338.1922.
1
1440, 1360, 1250, 1170, 1100, 835, 775, 700 cmꢁ1. H
NMR (CDCl3) d: 0.07 (6H, s), 0.84 (9H, s), 1.44 (1H, m),
1.52 (3H, s), 1.87 (1H, m), 2.98 (1H, dd, J¼3.2, 10.7 Hz),
3.41 (2H, m), 3.76 (3H, s), 7.20–7.47 (5H, m). MS
(SIMS): m/z 353 (M++1), 335, 303, 203 (100%), 175, 121,
73. HRMS calcd for C19H33O4Si 353.2149, found 353.2152.
4.1.2.10. Methyl (anti)-3-hydroxy-3-phenyl-2-[2-(tert-
butyldimethylsilyloxy)-ethyl]-butyrate (9b). Yield 56%.
Colorless oil. IR (film): 3505, 2955, 2855, 1715, 1500,
4.1.2.4. Methyl (anti)-3-hydroxy-3-phenyl-2-[2-(tert-
butyldimethylsilyloxy)-ethyl]-propionate (3b). Yield
45%. Colorless oil. IR (film): 3470, 2955, 2850, 1735, 1255,
1100, 835, 775, 700 cmꢁ1. 1H NMR (CDCl3) d: 0.03 (6H, s),
0.87 (9H, s), 1.63 (1H, m), 1.82 (1H, m), 2.96 (1H, dt, J¼7.4,
4.8 Hz), 3.56 (2H, m), 3.66 (3H, s), 4.83 (1H, d, J¼7.4 Hz),
7.33 (5H, m). MS (EI): m/z 338 (M+), 281, 263, 249, 189,
175 (100%), 89. HRMS calcd for C18H30O4Si 338.1913,
found 338.1920.
1
1435, 1360, 1250, 1170, 1105, 835, 775, 700 cmꢁ1. H
NMR (CDCl3) d: 0.03 (6H, s), 0.88 (9H, s), 1.47 (3H, s),
1.98 (2H, dt, J¼8.2, 5.6 Hz), 3.04 (1H, dt, J¼8.2, 6.0 Hz),
3.34 (3H, s), 3.46–3.72 (2H, m), 7.14–7.40 (5H, m). MS
(SIMS): m/z 353 (M++1), 335, 303, 203 (100%), 175, 121,
73. HRMS calcd for C19H33O4Si 353.2149, found 353.2154.
4.1.2.11. (syn)-3-(3,4-Dimethoxy-a-hydroxybenzyl)-
dihydrofuran-2-one (11a). Yield 46%. Colorless needles
(ethyl acetate–hexane, mp 116–117 ꢀC). IR (KBr): 3490,
4.1.2.5. Methyl (syn)-3-(3,4-dimethoxyphenyl)-3-hy-
droxy-2-methylpropionate (5a). Yield 46%. Colorless oil.

H. Sai et al. / Tetrahedron 63 (2007) 10345–10353
10353
2950, 1765, 1595, 1515, 1460, 1235, 1130, 1030, 810,
m/z 432 (M+), 414, 300, 266, 181, 166 (100%), 151, 95.
HRMS calcd for C23H28O8 432.1784, found 432.1778.
1
760 cmꢁ1. H NMR (CDCl3) d: 2.02 (1H, m), 2.43 (1H,
m), 2.92 (1H, dt, J¼2.8, 9.5 Hz), 3.88 (3H, s), 3.89 (3H, s),
4.19 (1H, dt, J¼8.8, 7.3 Hz), 4.35 (1H, dt, J¼3.6, 8.8 Hz),
5.33 (1H, d, J¼2.8 Hz), 6.90 (3H, m). MS (EI): m/z 252
(M+), 167 (100%), 139. Anal. calcd for C13H16O5: C,
61.90; H, 6.39. Found: C, 61.94; H, 6.51.
4.1.2.18.
(anti)-3-[(3,4-Dimethoxyphenyl)hydroxy-
methyl]-4-(3,4,5-trimethoxybenzyl)dihydrofuran-2-one
(17b). Yield 50%. Colorless needles (ethyl acetate–hexane,
mp 116–118 ꢀC). IR (KBr): 3490, 2940, 1765, 1590, 1515,
1465, 1240, 1125, 1025, 815, 765 cmꢁ1. H NMR (CDCl3)
1
4.1.2.12. (anti)-3-(3,4-Dimethoxy-a-hydroxybenzyl)-
dihydrofuran-2-one (11b). Yield 42%. Colorless oil. IR
(film): 3505, 2940, 1765, 1595, 1515, 1460, 1255, 1140,
d: 2.18 (2H, m), 2.49–2.71 (2H, m), 3.80 (9H, s), 3.88 (3H,
s), 3.90 (3H, s), 4.08–4.21 (2H, m), 4.84 (1H, d, J¼7.8 Hz),
6.08 (2H, s), 6.85–6.99 (3H, m). MS: m/z 432 (M+), 414,
300, 266 (100%), 251, 181, 166, 151, 95. Anal. calcd for
C23H28O8: C, 63.88; H, 6.53. Found: C, 63.84; H, 6.51.
1
1025, 820, 765 cmꢁ1. H NMR (CDCl3) d: 1.98 (2H, m),
2.91 (1H, dt, J¼8.8, 9.8 Hz), 3.88 (3H, s), 3.89 (3H, s),
4.07–4.34 (2H, m), 4.78 (1H, d, J¼8.8 Hz), 6.83 (1H, d,
J¼8.2 Hz), 6.90 (1H, dd, J¼8.2, 2.0 Hz), 6.96 (1H, d,
J¼2.0 Hz). MS (EI): m/z 252 (M+), 167 (100%), 139.
HRMS calcd for C13H16O5 252.0998, found 252.1002.
References and notes
1. Faulkner, D. J. Synthesis 1971, 175–189.
4.1.2.13. (syn)-3-(1-Hydroxybut-2-enyl)-dihydro-
furan-2-one (13a). Yield 25%. Colorless oil. IR (film):
2. Kelly, S. E. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 1,
pp 730–817.
1
3450, 2950, 1765, 1600, 1380, 1180, 1030 cmꢁ1. H NMR
(CDCl3) d: 1.75 (3H, d, J¼6.4 Hz), 2.15–2.37 (2H, m),
2.76 (1H, dt, J¼3.2, 9.6 Hz), 4.26 (1H, m), 4.36 (1H, m),
4.60 (1H, m), 5.48 (1H, m), 5.80 (1H, m). MS: m/z 156
(M+), 138 (100%), 123, 86, 71. HRMS calcd for C8H12O3
156.0786, found 156.0792.
3. For instance, the methanesulfonate of the syn-a-substituted-
b-hydroxyphenylpropionate syn-1 was treated with DBU to
afford the (E)-a-substituted cinnamate E-2 stereoselectively
in 97% yield as the sole product. However, the corresponding
anti-methanesulfonate anti-1 afforded a mixture of (Z)- and
(E)-a-substituted cinnamates Z-2 and E-2 (32:68) in 98%
yields.
4. Krebs, A.; Swienty-Busxh, J. Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
UK, 1991; Vol. 5, pp 950–958.
4.1.2.14. (anti)-3-(1-Hydroxybut-2-enyl)-dihydro-
furan-2-one (13b). Yield 17%. Colorless oil. IR (film):
1
3445, 2945, 1760, 1605, 1380, 1185, 1025 cmꢁ1. H NMR
(CDCl3) d: 1.73 (3H, d, J¼6.1 Hz), 2.12 (1H, m), 2.28 (1H,
m), 2.68 (1H, m), 4.24 (2H, m), 4.39 (1H, m), 5.54 (1H, m),
5.82 (1H, m). MS: m/z 156 (M+), 138 (100%), 123, 86, 71.
HRMS calcd for C8H12O3 156.0786, found 156.0791.
5. Matsuda, I.; Murata, S.; Izumi, Y. Bull. Chem. Soc. Jpn. 1979,
52, 2389–2393.
6. Haraguchi, K.; Tanaka, H.; Itoh, Y.; Miyasaka, T. Tetrahedron
Lett. 1991, 32, 777–780.
4.1.2.15. (syn)-3-(1-Hydroxy-2-methylpropyl)-dihydro-
furan-2-one (15a). Yield 9%. Colorless oil. IR (film):
7. (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–
4408; (b) Ando, K. J. Org. Chem. 1998, 63, 8411–8416; (c)
Tago, K.; Kogen, H. Tetrahedron 2000, 56, 8825–8831.
8. Pachamuthu, K.; Vankar, Y. D. Tetrahedron Lett. 1998, 39,
5439–5442.
9. (a) Hoye, T. R.; Kurth, M. J. J. Org. Chem. 1980, 45, 3549–
3553; (b) Shimagaki, M.; Shiokawa, M.; Sugai, K.;
Teranaka, T.; Nakata, T.; Oishi, T. Tetrahedron Lett. 1988,
29, 659–662.
3460, 2965, 1760, 1380, 1180, 1025 cmꢁ1 1H NMR
.
(CDCl3) d: 0.92 (3H, d, J¼6.6 Hz), 1.04 (3H, d, J¼
6.6 Hz), 1.69 (1H, m), 2.18 (1H, m), 2.48 (1H, m), 2.80 (1H,
dt, J¼2.5, 10.1 Hz), 3.83 (1H, dd, J¼2.5, 8.8 Hz), 4.25 (1H,
m), 4.39 (1H, m). MS: m/z 159 (M++1), 140, 130, 115, 86
(100%), 71. HRMS calcd for C8H15O3 159.1022, found
159.1025.
10. Corey, E. J.; Letavic, M. A. J. Am. Chem. Soc. 1995, 117, 9616–
9617.
4.1.2.16. (anti)-3-(1-Hydroxy-2-methylpropyl)-dihydro-
furan-2-one (15b). Yield 71%. Colorless oil. IR (film):
11. Sai, H.; Ohmizu, H. Tetrahedron Lett. 1999, 40, 5019–5022.
12. Kauren, J. Angew. Chem., Int. Ed. Engl. 1987, 26, 773–774.
13. The Z-isomer was treated with DCC and EDC in the presence
of CuCl2 in toluene at 80 ꢀC, and E-isomer was not obtained
at all.
14. (a) Corey, E. J.; Anderson, N. H.; Carlson, R. M.; Paust, J.;
Vedejs, E.; Vlattas, I.; Winter, R. E. J. Am. Chem. Soc. 1968,
90, 3245–3247; (b) Alexandre, C.; Rouessac, F. Bull. Soc.
Chim. Fr. 1971, 1837–1840.
3500, 2965, 1755, 1380, 1175, 1000 cmꢁ1 1H NMR
.
(CDCl3) d: 0.94 (3H, d, J¼6.6 Hz), 1.06 (3H, d, J¼
6.6 Hz), 1.80 (1H, m), 2.05 (1H, m), 2.30 (1H, m), 2.68
(1H, dt, J¼11.6, 8.7 Hz), 3.61 (1H, dd, J¼3.4, 8.7 Hz), 4.22
(1H, m), 4.42 (1H, dt, J¼1.9, 8.9 Hz). MS: m/z 159 (M++1),
140, 115, 86 (100%), 71. HRMS calcd for C8H15O3
159.1022, found 159.1026.
€
4.1.2.17. (syn)-3-[(3,4-Dimethoxyphenyl)hydroxy-
methyl]-4-(3,4,5-trimethoxybenzyl)dihydrofuran-2-one
(17a). Yield 47%. Colorless oil. IR (film): 3485, 2940, 1765,
15. Dabritz, E. Angew. Chem., Int. Ed. Engl. 1966, 5, 470–477.
16. (a) Dolinnaya, N. G.; Tsytovich, A. V.; Sergeev, V. N.;
Gertsuk, M. N.; Shabarova, Z. A. Bioorg. Khim. 1990, 16,
1183–1194; (b) Gertsuk, M. N.; Sergeev, V. N.; Tsytovich,
A. V.; Dolinnaya, N. G.; Kukhar, V. P. Bioorg. Khim.
1990, 16, 1268–1276.
1
1590, 1515, 1465, 1230, 1125, 1025, 815, 750 cmꢁ1. H
NMR (CDCl3) d: 2.26–2.48 (2H, m), 2.68 (1H, m), 2.82
(1H, m), 3.77 (6H, s), 3.80 (6H, s), 3.86 (3H, s), 3.87 (3H,
s), 3.96 (1H, m), 4.34 (1H, dd, J¼7.7, 8.8 Hz), 5.31 (1H,
d, J¼2.8 Hz), 6.06 (2H, s), 6.78 (2H, s), 6.88 (1H, s). MS:
17. Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org.
Chem. 1961, 26, 2525–2528.