Diastereoselective construction of azetidin-2-ones by electrochemical intramolecular C-C bond forming reaction

Article abstract of DOI:10.1016/j.tet.2009.09.087

A convenient method for synthesis of optically active azetidin-2-ones using electrochemical oxidation has been exploited. The method consists of a diastereoselective intramolecular C-C bond forming reaction between active methylene and methyne groups thro

Full text of DOI:10.1016/j.tet.2009.09.087

Tetrahedron 65 (2009) 9742–9748
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective construction of azetidin-2-ones by electrochemical
intramolecular C–C bond forming reaction
*
Daishirou Minato, Satoshi Mizuta, Masami Kuriyama, Yoshihiro Matsumura, Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method for synthesis of optically active azetidin-2-ones using electrochemical oxidation
has been exploited. The method consists of a diastereoselective intramolecular C–C bond forming re-
action between active methylene and methyne groups through an electrochemical system in which
positive iodine species acted as mediators under mild conditions.
Received 4 September 2009
Received in revised form
22 September 2009
Accepted 22 September 2009
Available online 23 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Azetidinone
Electrochemical oxidation
Diastereoselective
Carbon–carbon bond forming reaction
Cyclization
OH
N
O
O
Me
O
1. Introduction
I2
H
CO2Et
CO2Et
R3
CO2Et
CO2Et
R3
CO2Et
CO2Et
R3
NaOEt
Me
Me
Since the discovery of thienamycin (1),1 a variety of synthetic
methods of 1 and its precursors 2 have been exploited (Scheme
1).2 However, new efficient synthetic methods are still of great
interest because of economic reasons and the continuing need
N
N
a: R3=Ph
b: R3=p-MeOPh
c: R3= PhCH2
O
O
5a-c
3a-c
4a-c
ð1Þ
for novel b-lactamase inhibitors. In 1985, Simig and co-workers
reported that the construction of N-protected azetidin-2-ones
4a–c from N-arylated or N-benzylated N-(3-oxobutyryl)amino-
malonate diethyl esters 3a–c, which are equilibrated with pyr-
rolidine-2-ones 5a–c, was achieved by I2 in the presence of
NaOEt (Eq. 1).3
Although this reaction is very convenient for the construction of
azetidin-2-oneskeleton, therehasbeennoreportforitschiralversion.
We report herein a convenient electrochemical diastereoselective
construction of azetidin-2-ones 4d–f possessing acetyl group at the
3-position and two alkoxylcarbonyl groups at the 4-position from
easily available N-(3-oxobutyryl)aminomalonate esters 3d–f pos-
sessing a chiral auxiliary on a nitrogen atom (Scheme 2). Scheme 2
also shows our strategy for the transformation of 4d–f to enantio-
merically pure 4-methoxy-3-(10-silyloxyethyl)azetidin-2-one (2a),4
which is an important key synthetic intermediate for 1.
OR2
OH
OR1
H H
H
1'
Me
Me
NH2
4
S
N
NH
O
O
CO2H
2
1 thienamycin
diastereoselective
OR2
Scheme 1.
O
OH
N
O
Me
O
connection
H
CO2R4
CO2R4
H
OMe
CO2R4
CO2R4
CO2R4
1'
transformation
Me
4
Me
CO2R4
Me
3
2
4
1N
NH
N
O
O
R*
3d-f
R*
5d-f
O
R*
4d-f
2a
R2=SiMe2-t-Bu
* Corresponding author.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
Scheme 2. Strategy for preparation of enantiomerically pure azetidin-2-one 4.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.087

D. Minato et al. / Tetrahedron 65 (2009) 9742–9748
9743
Table 1
Preparation of 2-pyrrolidinones 5d–f
Entry
R*
R4
Condition
Yieldb (%) of 6
Yieldb (%) of 5
Step 1
rt
Step 2
80 ꢀCa
Me
(R)
Ph
1
2
Et
Toluene
Toluene
6d
6e
5d
93
79
t-Bu
80 ꢀCa
80 ꢀCa
80 ꢀCa
5e
5f
88
87
83
94
Me
(R)
3
t-Bu
rt
CH2Cl2
6f
Php-OMe
a
Temperature of bath.
Isolated yield.
b
2. Results and discussion
2.1. Preparation of chiral pyrrolidin-2-ones 5d–f
2.3. Reaction mechanism
Plausible reaction mechanism for electrochemical cyclization of
3e is shown in Scheme 3. Briefly, anodically generated positive io-
dine species ‘Iþ’ react with 3e to afford iodinated intermediate A,5
which is transformed to enolate B6 by cathodically generated base
‘EGB’.7 Finally cyclization of B affords thermodynamically stable
Pyrrolidin-2-ones 5d–f were prepared in good to high yields
using similar method for preparation of 5a–c (Eq. 2).3 The results
are shown in Table 1.
Step 1
Step 2
diketene
Me
HO
N
CO2R4
CO2R4
CO2R4
CO2R4
CO2R4
Et3N
R* NH2
+
Br
R*HN
CO2R4
ð2Þ
O
MeCN
Et3N
solvent
R*
5d-f
6d-f
2.2. Diastereoselective construction of azetidin-2-ones 4d–f
3S–4e diastereoselectively. The reason why electrochemical re-
action in Table 2 shows higher yields and diastereoselectivity than
the corresponding chemical reaction might be explainable by the
characteristics of ‘EGB’. Since ‘EGB’ on cathode simultaneously
generated along with ‘Iþ’ on anode in the electrochemical reaction,
the electrochemical reaction holds almost neutral. On the other
hand, the chemical reaction is always too basic. The strong basicity
in the chemical reaction might lower the yield and diaster-
eoselectivity of 4e.
Chemical intramolecular C–C bond forming reaction of 5d–f
(Method A) and the corresponding electrochemical reaction
(Method B) were examined under various conditions (Eq. 3). The
results are summarized in Table 2.
O
Me
Method A
I2 (1.0 equiv)
NaOEt (3.0 equiv)
in solvent, 1 h
HO
CO2R4
CO2R4
H
CO2R4
CO2R4
S
O
N
N
ð3Þ
O
Me
R
Me
R
Method B
Table 2
R5
R5
−2e, 4 F/mol
NaI (0.5 equiv) in solvent
Diastereoselective cyclization of pyrrolidin-2-ones 5d–f
5d-f
4d-f
Entry Substrate Methoda Conditions
Solvent Temp
Product 4
When chemical cyclization of diethyl ester 5d was attempted
Yieldb (%) dec (%)
in ethanol and acetonitrile at rt, azetidin-2-one 4d was not
obtained at all (entries 1 and 3), however increase of temperature
to 85 ꢀC lead to the formation of 4d in low yields with moderate
diastereoselectivities (entries 5 and 7). On the other hand, elec-
trochemical cyclization of 5d at ambient temperature proceeded
to afford 4d in moderate yields (entries 2, 4, 9, and 11). Heat
generated during electrochemical oxidation might affect the cy-
clization. Although the yield of 4d by electrochemical cyclization
of 5d in ethanol was not improved at 85 ꢀC compared with at
ambient temperature (entries 2 and 6), in acetonitrile somewhat
better yield was obtained than that at ambient temperature
(entries 4 and 8). The best result was obtained in acetonitrile at
85 ꢀC (entry 8). These optimized conditions were applicable to
cyclization of di-tert-butyl esters 5e and 5f to afford azetidin-2-
ones 4e and 4f in high yields with good to high diaster-
eoselectivities (entries 10 and 12). Recrystallization of 4e from
a mixture of diethyl ether and n-hexane (1/2 v/v) afforded 3S–4e
as a single diastereoisomer.
1
2
3
4
5
6
7
8
5d
5d
5d
5d
5d
5d
5d
5d
5e
5e
5f
A
B
A
B
A
B
A
B
B
B
B
B
EtOH
EtOH
MeCN
MeCN
EtOH
rt
4d
4d 23
4d
4d 41
0
d
a.t.d
rt
58
d
0
a.t.d
58
48
59
48
68
79
80
70
74
85 ꢀCe 4d 30
85 ꢀCe 4d 19
85 ꢀCe 4d 12
85 ꢀCe 4d 56
EtOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
a.t.d
85 ꢀCe 4e
a.t.d
4f
85 ꢀCe 4f
4e
33
94
67
89
10
11
12
5f
a
Method A: A solution of 5 (0.5 mmol), I2 (0.5 mmol), and NaOEt (1.5 mmol) in
solvent (5 mL) was stirred for 1 h. Method B: 4 F/mol of electricity was passed
through a solution of 5 (0.5 mmol) and NaI (0.5 mmol) in solvent (5 mL).
b
Isolated yield (%).
c
Determined by 1H NMR.
d
Ambient temperature (The temperature of the reaction mixture gradually raised
from rt to ca. 50 ꢀC as electricity was passed).
e
Temperature of bath.

9744
D. Minato et al. / Tetrahedron 65 (2009) 9742–9748
2.5. Determination of absolute stereoconfiguration for 7e
Recrystallization of 7e afforded 3S,10R-7e as
single di-
O
O
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
I
Me
Me
a
N
N
astereoisomer, whose absolute stereoconfiguration was de-
I+
O
R*
H+
O
R*
A
anode
termined to be 10R by X-ray analysis (Fig. 1).8
cathode
+e
3e
EGBH+
HO
Me
CO2-t-Bu
CO2-t-Bu
−2e
I−
+e
N
R*
O
EGB
1/2H2
1/2H2
+
O−
O-t-Bu
CO2-t-Bu
O
5e
CO2-t-Bu
CO2-t-Bu
O
H
Me
I
R
Me
N
N
O
R*
O
R*
3R-4e
O
B
CO2-t-Bu
CO2-t-Bu
H
Me
EGB
S
N
O
3S-4e
R*
Scheme 3. Plausible reaction mechanism of electrochemical cyclization.
In fact, equilibration of 3S–4e and 3R–4e in the reaction con-
ditions was confirmed by 1H NMR (Scheme 4). Although dia-
stereomerically pure 3S–4e was not epimerized in CDCl3,
epimerization of 3S–4e in the presence of potassium carbonate
was observed to reach to the equilibrium. Although we cannot
deny some effect of kinetic control on the diastereoselectivities in
these cyclization, thermodynamic control could rationalize the
diastereoselectivities.
Figure 1. Absolute stereoconfiguration of 7e.
K2CO3
As a result, it was deduced that major isomer of 4e was 3S–4e.
3S-4e
3S-4e
100% de
3S-4e
+ 3R-4e
CDCl3
at 25 °C
100% de
CDCl3
at 25 °C
87 : 13
2.6. Stereochemical course
Scheme 4. Equilibration of 3S–4e and 3R–4e.
The diastereoselectivity might be explained by thermodynam-
ical stability of 3S–4e compared with 3R–4e. Namely, when 10R-
phenylethyl group occupied the lower side of azetidine ring shown
as (b) and (d) in Figure 2, there might be steric repulsion between
tert-butyl group and phenyl group. Additionally, steric repulsion
between acetyl group and 10R-phenylethyl group in 3S–4e might
occur ((b) in Figure 2). On the other hand, when 10R-phenylethyl
group occupied the upper side of azetidine ring ((a) and (c) in
Figure 2), there might be steric repulsion between acetyl group and
10R-phenylethyl group in 3R–4e ((c) in Figure 2). Accordingly, 3S–4e
shown as (a) in Figure 2 is the most stable conformation. Also,
bulkier di-tert-butyl ester 4e could be obtained with better dia-
stereoselectivity than that of diethyl ester 4d.
2.4. Diastereoselective reduction
Diastereoselective reduction of acetyl group in 4d,e was carried
out under several reaction conditions (Eq. 4). The results are
summarized in Table 3.
O
HO
R
O
CO2R4
H
CO2R4
CO2R4
H
H
OH
OEt
Me
CO2R4 reduction
Me
Me
S
S
+
N
N
N
O
O
Me
O
Me
O
Me
R
R
R
4d,e
8 , 29% yield from 4d
7d,e
ð4Þ
H
S
CO2-t-Bu
H
Me
CO2-t-Bu
H
S
R
O
Me
Ph
N
O
CO2-t-Bu
N
O
CO2-t-Bu
Ph
Me
Although NaBH4 majorly reduced ethoxycarbonyl group instead
Me
Me
O
H
R
of acetyl group in diethyl ester 4d to afford 8 (entry 1), NaBH4 or
DIBAH in THF reduced acetyl group in di-tert-butyl ester 4e to af-
ford 7e in good to high diastereoselectivity. Epimerization of 4e at
the 3-position was not observed under the reaction conditions.
(a) 3S-4e
(b) 3S-4e
Me
O
CO2-t-Bu
CO2-t-Bu
O
H
R
Me
R
CO2-t-Bu
Ph
O
R
N
O
Table 3
H
N
CO2-t-Bu
Diastereoselective reduction of 3-acetylazetidin-2-ones 4d,e
H
Ph
Me
H
R
Entry Substrate Reductant Condition
Solvent Temp
Product 7
(c) 3R-4e
(d) 3R-4e
Yielda (%) deb (%)
Figure 2. Steric hindrance of 3S–4e and 3R–4e.
1
2
3
4
5
6
4d
4e
4e
4e
4e
4e
NaBH4
NaBH4
NaBH4
NaBH4
DIBAH
DIBAH
MeOH
MeOH
THF
THF
THF
rt
rt
rt
7d
7
d
7e 89
7e 85
7e 83
7e 48
7e 46
12
76
84
80
78
Plausible stereochemical course for the NaBH4 reduction of 4e
are shown in Scheme 5. Sodium ion chelates with the two carbonyl
groups, due to this and also the steric repulsion on the re-face be-
tween the hydride ion and the tert-butyl group, the hydride attack
therefore takes place on the si-face to afford 10R–7e diastereoselectively.
ꢁ20 ꢀ
C
rt
THF
0 ꢀ
C
a
Isolated yield (%).
b
Determined by 1H NMR.

D. Minato et al. / Tetrahedron 65 (2009) 9742–9748
9745
Higher diastereoselectivity in THF than MeOH seems to support
chelation (entries 2 and 3 in Table 3).
were measured on a Varian Gemini 300 and 400 spectrometer with
TMS as an internal standard. 13C NMR spectra were measured on
a Varian Gemini 400 spectrometer with TMS as an internal stan-
dard. IR spectra were obtained on a Shimadzu FTIR-8100A. Ele-
mental analyses were carried in Center for Instrumental Analysis,
Nagasaki University. Mass spectra were obtained on a JEOL JMS-DX
303 instrument. Specific rotations were measured with Jasco DIP-
1000. All melting points were measured on MICRO MELTING POINT
APPARATUS (Yanaco) and are uncorrected.
All solvents were used as supplied without further purification.
Diethyl bromomalonate, 1R-phenylethylamine, and 1R-(4-metho-
xyphenyl)ethylamine are commercially available. Di-tert-butyl
bromomalonate was prepared from di-tert-butyl malonate by
known procedure.11
HO
R
H
CO2-t-Bu
CO2-t-Bu
Me
S
N
O
Me
H-
O
H
si-face
Me
t-BuO2C
R
H
N
1'R-7e
Na+
O
HO
S
t-BuO2C
H
Me
CO2-t-Bu
CO2-t-Bu
H-
Me
S
re-face
N
O
Me
R
4.2. Preparation of aminomalonate 6d–f: general procedure
1'S-7e
Scheme 5. Plausible stereochemical course for NaBH4 reduction of 3S–4e.
To a solution of 1R-phenylethylamine (3.05 g, 25 mmol) and
Et3N (2.53 g, 25 mmol) in acetonitrile (25 mL) was added diethyl
bromomalonate (8.13 g, 34 mmol). After stirring for 6 h, to the
resulting mixture was poured water (30 mL). Organic portion of
aqueous layer was extracted with dichloromethane (3ꢂ25 mL) and
washed with satd aq NaCl (25 mL). After drying the organic layer
over MgSO4, solvent was removed in vacuo, and residue purified by
silica gel column chromatography (n-hexane:AcOEt¼10:1) to afford
diethyl (1R-phenylethyl)aminomalonate (6d)12 in 79% yield.
2.7. Preparation of enantiomerically pure azetizin-2-one 2a
from 10R-7e
Enantiomerically pure 4-methoxy-3-(10-silyloxyethyl)azetidin-
2-one (2a) was prepared from 10R–7e by procedure shown in
Scheme 6. Namely, acetylation of 10R–7e afforded 9, which was then
subjected to acid catalyzed hydrolysis to give dicarboxylic acid 10 in
quantitative yield. Decarboxylation of 10 afforded monocarboxylic
acid 11, which was then transformed into 4R-methoxylated azeti-
dinone 12 in 73% yield by the non-Kolbe electrolysis.9,10 Silylation of
12 and successive hydrogenolysis of chiral auxiliary of 13 afforded
desired azetidinone 2aas an enantiomericallypure form(Scheme 6).
4.2.1. Di-tert-butyl(1R-phenylethyl)aminomalonate (6e). Yellow oil;
28.3
[a
]
þ58.8 (c¼1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 1.38 (d,
D
J¼6.6 Hz, 3H), 1.42 (s, 9H), 1.47 (s, 9H), 2.37 (br s, NH), 3.69 (s, 1H),
3.79 (q, J¼6.6 Hz,1H), 7.20–7.39 (m, 5H); IR (neat) 3350, 2978, 2932,
2342, 1750, 1734, 1475, 1493, 1475, 1455, 1395, 1140, 1007, 847,
OAc
OAc
OAc
H
H
H
R
R
R
CO2-t-Bu
CO2-t-Bu CH2Cl2
CO2H
CO2H
CO2H
TFA,
AcCl
Me
Me
Me
S
S
S
DMAP
2,4,6-collidine
160 °C, 1 h
1'R-7e
N
N
N
rt, 2 h
pyridine
rt, 2 h
O
Me
O
Me
O
Me
R
R
R
9, 75% yield
10, quant. yield
11, quant. yield
OH
OSiMe2-t-Bu
OSiMe2-t-Bu
1) −2e, NaOMe
MeOH/MeCN
(1/4)
H
R
OMe
H
R
S
H
R
S
R
TBDMSCl, DMAP
DMF, rt, 24 h
Na
liq NH3
R
OMe
OMe
Me
R
S
Me
Me
N
N
O
NH
O
2) chromatography
O
Me
THF
−78 °C
30 min
R
R
Me
12, 73% yield
4R:4S=100:0
13, 65% yield
2a, 95% yield
Scheme 6. Preparation of azetidinone 2a from 1’R–7e.
3. Conclusion
702 cmꢁ1; HRMS (EI) calcd for C19H28NO4 (Mþ) 335.2097, found:
335.2095.
A convenient method for the synthesis of optically active aze-
tidin-2-ones using electrochemical oxidation has been exploited.
The method consists of diastereoselective intramolecular C–C bond
forming reaction between active methylene and methyne groups
by electrochemical mediator system in which positive iodine spe-
cies act as mediators under mild conditions.
4.2.2. Di-tert-butyl [1R-(4-methoxyphenyl)ethyl]aminomalonate (6f).
Yellow oil; 1H NMR (300 MHz, CDCl3)
d
1.36 (d, J¼6.6 Hz, 3H) 1.42 (s,
9H), 1.47 (s, 9H), 2.38 (br s, NH), 3.75 (q, J¼6.6 Hz, 1H), 3.80 (s, 3H),
6.85 (d, J¼8.7 Hz, 2H), 7.25 (d, J¼8.7 Hz, 2H); IR (neat) cmꢁ1; HRMS
(EI) calcd for C20H31NO5 (Mþ) 365.2202, found: 365.2214.
4. Experimental section
4.1. General
4.3. Preparation of chiral pyrrolidin-2-ones 5d–f:
General procedure
Electrochemical reactions were carried out using DC Power
Supply (GP 050-2) of Takasago Seisakusho, Inc. 1H NMR spectra
To a solution of 6d (5.59 g, 20 mmol) and Et3N (2.02 g, 20 mmol)
in toluene (30 mL) was slowly added dropwise diketene (1.7 mL,

9746
D. Minato et al. / Tetrahedron 65 (2009) 9742–9748
22 mmol) at 0 ꢀC. After the solution was stirred at 80 ꢀC for 1 h, the
solvent was removed in vacuo at rt. The residue was purified by
silica gel column chromatography (n-hexane/AcOEt¼1:1) to afford
diethyl 3-hydroxy-3-methyl-1-(10R-phenylethyl)pyrrolidin-5-one-
2,2-dicarboxylate (5d) in 93% yield.
gel column chromatography (n-hexane/AcOEt¼1:1) to afford 3S–4e
in 94% yield with 80% de, which was recrystallized from a mixture
of diethyl ether and n-hexane (1/2 v/v) to give enantiomerically
pure 3S–4e.
4.4.3. Diethyl
3S-acetyl-1-(10R-phenylethyl)azetidin-2-one-4,4-di-
4.3.1. Diethyl 3-hydroxy-3-methyl-1-(10R-phenylethyl)pyrrolidin-5-
carboxylate (4d) (3S:3R¼74:26). Yellow oil; 1H NMR (300 MHz,
one-2,2-dicarboxylate (5d) (a mixture of two diastereomers). White
CDCl3)
d
0.94 (t, J¼7.2 Hz, 2.22H), 1.06 (t, J¼7.2 Hz, 0.78H), 1.32 (t,
solid; mp 56–61 ꢀC; 1H NMR (400 MHz, CDCl3)
d
0.93 and 0.99 (2t,
J¼7.2 Hz, 3H), 1.74 (d, J¼7.2 Hz, 0.78H), 1.87 (d, J¼7.2 Hz, 2.22H),
2.31 (s, 0.78H), 2.35 (s, 2.22H), 3.47–3.62 (m, 0.74H), 3.78–3.90 (m,
0.74H), 3.90–4.02 (m, 0.26H), 4.03–4.15 (m, 0.26H), 4.15–4.45 (m,
2H), 4.57–4.70 (m, 0.74H), 4.75–4.85 (m, 0.26H), 4.68 (s, 0.26H),
4.84 (s, 0.74H), 7.20–7.45 (m, 5H); IR (neat): 2984, 2938, 1779, 1455,
1393, 1300, 1280, 1240,1180, 1096, 1057, 1028, 903, 860, 762,
702 cmꢁ1; HRMS (EI) calcd for C19H23NO6 (Mþ) 361.1525, found:
361.1525.
J¼7.3 Hz, 3H), 1.27 and 1.31 (2t, J¼7.3 Hz, 3H), 1.49 and 1.50 (2s, 3H),
1.81 and 1.84 (2d, J¼7.2 Hz, 3H), 2.55–2.80 (m, 2H), 3.68–4.40 (m,
5H), 4.75 and 4.93 (2q, J¼7.3 Hz, 1H), 7.10–7.40 (m, 5H); IR (neat):
3400, 2984, 2940, 1736, 1707, 1686, 1410, 1269, 1231, 1079, 1098,
1053, 704 cmꢁ1; HRMS (EI) calcd for C19H25NO6 (Mþ) 363.1682,
found: 363.1684.
4.3.2. Di-tert-butyl 3-hydroxy-3-methyl-1-(10R-phenylethyl)pyrrolidin-5
-one-2,2-dicarboxylate (5e) (a mixture of two diastereomers). White
4.4.4. Di-tert-butyl 3S-acetyl-1-(10R-phenylethyl)azetidin-2-one-4,4-
26.2
solid; mp 153–160 ꢀC; 1H NMR (400 MHz, CDCl3)
d
1.11 and 1.24 (2s,
dicarboxylate (4e). White solid; mp 140–142 ꢀC; [
a
]
D
ꢁ6.1 (c 1.0,
9H), 1.41 and 1.51 (2s, 9H), 1.48 and 1.63 (2s, 3H), 1.81 and 1.84 (2d,
J¼7.3 Hz, 3H), 2.52–2.74 (m, 2H), 3.54 and 4.03 (2s, 1H, OH), 4.76 and
5.02 (2q, J¼7.3 Hz, 1H), 7.15–7.40 (m, 5H); 13C NMR (100 MHz, CDCl3)
CHCl3); 1H NMR (300 MHz, CDCl3)
J¼7.2 Hz, 3H), 2.35 (s, 3H), 4.66 (q, J¼7.2 Hz, 1H), 4.86 (s, 1H), 7.18–
7.40 (m, 5H); 13C NMR (100 MHz, CDCl3)
22.8, 27.0, 27.8, 30.4, 57.0,
d 1.07 (s, 9H), 1.55 (s, 9H), 1.85 (d,
d
d
19.2, 20.1, 23.5, 24.0, 27.3, 27.5, 27.8, 27.9, 46.1, 46.2, 54.5, 55.7, 76.5,
66.5, 67.2, 83.8, 83.9, 125.9, 127.2, 128.7, 143.0, 162.7, 164.9, 165.3,
197.8; IR (neat): 2980, 2930, 1765, 1718, 1495, 1394, 1371, 1001, 970,
900, 851, 764, 702 cmꢁ1; Anal. Calcd for C23H31NO6: C, 66.17; H,
7.48; N, 3.35. Found: C, 65.79; H, 7.62; N, 3.31.
80.0, 84.0, 84.1, 84.5, 84.7, 126.2, 126.3, 126.4, 126.6, 128.1, 142.2, 142.4,
166.3, 166.6, 166.7, 167.1, 174.0, 174.1; IR (neat): 3400, 2980, 2938, 1730,
1692, 1395, 1302, 1250, 1157, 1024, 754, 696 cmꢁ1; Anal. Calcd for
C23H33NO6: C, 65.85; H, 7.93; N, 3.34. Found: C, 66.25; H, 8.14; N, 3.33.
4.4.5. Di-tert-butyl 3S-acetyl-1-[10R-(4-methoxyphenyl)ethyl]azetidin-2-
23.8
4.3.3. Di-tert-butyl 3-hydroxy-1-[10R-(4-methoxyphenyl)ethyl]-3-methyl-
pyrrolidin-5-one-2,2-dicarboxylate (5f) (a mixture of two diaster-
eomers). White solid; mp 186–187 ꢀC; 1H NMR (400 MHz, CDCl3)
one-4,4- dicarboxylate (4f). White solid; mp 107 ꢀC; [
a
]
D
þ3.0 (c
1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 1.13 (s, 9H),1.54 (s, 9H),1.82
(d, J¼7.2 Hz, 3H), 2.34 (s, 3H), 3.78 (s, 3H), 4.62 (q, J¼7.2 Hz, 1H),
4.82 (s, 1H), 6.84 (d, J¼8.7 Hz, 2H), 7.22 (d, J¼8.7 Hz, 2H); IR (neat):
2980, 2936, 1771, 1734, 1615, 1559, 1541, 1514, 1474, 1395, 1370,
1302, 1248, 1159, 1032, 831 cmꢁ1; HRMS (EI) calcd for C24H33NO7
(Mþ): 447.2257, found: 447.2268.
d
1.19 and 1.30 (2s, 9H), 1.47 and 1.53 (2s, 9H), 1.51 and 1.60 (2d,
J¼3.0 Hz, 3H), 1.80 and 1.82 (2d, J¼6.8 Hz, 3H), 2.55–2.72 (m, 2H),
3.52 and 3.90 (2s, 1H, OH), 3.74 and 3.75 (2s, 3H), 4.74 and 4.94 (2q,
J¼6.8 Hz, 1H), 6.75–6.85 (m, 2H), 7.22 and 7.31 (2d, J¼8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3)
d 19.4, 20.0, 23.6, 23.9, 27.4, 27.6, 27.9,
28.0, 46.2, 46.3, 54.2, 55.1, 55.2, 76.5, 76.6, 80.0, 80.2, 84.0, 84.1, 84.5,
84.6, 113.4, 113.5, 127.5, 128.0, 134.4, 134.6, 158.1, 158.3, 166.2, 166.6,
166.9, 167.0, 173.9, 174.0; IR (neat): 3400, 2980, 2038, 1750, 1732,
1720, 1700, 1868, 1615, 1559, 1514, 1474, 1395, 1370, 1339, 1302,
4.5. Diastereoselective reduction of 3S–4e
To a solution of 3S–4e (100 mg, 0.24 mmol) in tetrahydrofuran
(3 mL) was added NaBH4 (18 mg, 0.48 mmol). After stirring for 4 h
at ꢁ20 ꢀC, to the reaction mixture was added AcOEt (30 mL). The
resulting solution was washed with water (20 mL) and satd
aqueous NaCl (20 mL). The organic layer was dried over MgSO4
and the solvent was removed under reduced pressure. The residue
was subjected to silica gel column chromatography (n-hexane/
AcOEt¼1:1) to afford 10R-7e in 83% yield with 84% de, which was
recrystallized from diethyl ether to give enantiomerically pure
10R-7e.
1248, 1156, 1030, 910, 831, 735 cmꢁ1
C24H35NO7 (Mþ) 449.2414, found: 449.2400.
; HRMS (EI) calcd for
4.4. Preparation of chiral azetidin-2-ones 4d–f
4.4.1. Typical procedure for chemical method A (entry 5 in Table
2). To a solution of 5d (182 mg, 0.5 mmol) in ethanol (5 mL) were
added I2 (127 mg, 0.5 mmol) and Na (35 mg, 1.5 mmol). After stir-
ring for 1 h at 85 ꢀC, to the reaction mixture was added AcOEt
(30 mL). The resulting solution was washed with 5% Na2S2O3
(3ꢂ10 mL) and satd aqueous NaCl (10 mL). The organic layer was
dried over MgSO4 and the solvent was removed under reduced
pressure. The residue was subjected to silica gel column chroma-
tography (n-hexane/AcOEt¼1:1) to afford 3S–4d in 30% yield with
48% de.
4.5.1. 3S-(10R-Hydroxyethyl)-1-(10R-phenylethyl)azetidin-2-one-4,4-
dicarboxylic acid di-tert-butyl ester (7e). White solid; mp 151–
26.2
153 ꢀC; [
a
]
þ19.7 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 1.10
D
(s, 9H), 1.43 (d, J¼3.0 Hz, 3H),1.58 (s, 9H),1.85 (d, J¼5.4 Hz, 3H), 2.57
(d, J¼2.4 Hz, 1H), 3.78 (d, J¼6.9 Hz, 1H), 4.00–4.07 (m, 1H), 4.58 (q,
J¼5.4 Hz, 1H), 7.18–7.30 (m, 5H); IR (neat): 3500, 2980, 2936, 1759,
1736, 1495, 1456, 1395, 1370, 1343, 1250, 1156, 835, 758, 700 cmꢁ1
;
4.4.2. Typical procedure for electrochemical method B (entry 10 in
Table 2). In an undivided cell equipped with platinum plate elec-
trodes (1ꢂ2 cm2) was placed a solution of 5e (210 mg, 0.5 mmol)
and NaI (75 mg, 0.5 mmol) in acetonitrile (5 mL). A constant current
(100 mA) was passed through the cell externally warmed in oil-
bath (85 ꢀC). After 4 F/mol of electricity was passed, to the reaction
mixture was added AcOEt (30 mL). The resulting solution was
washed with 5% Na2S2O3 (3ꢂ10 mL) and satd aqueous NaCl (10 mL).
The organic layer was dried over MgSO4 and the solvent was re-
moved under reduced pressure. The residue was subjected to silica
HRMS (EI) calcd for C23H33NO6: C, 65.85; H, 7.93; N, 3.34. Found: C,
66.20; H, 8.07; N, 3.35.
4.6. Acetylation of 10R–7e
To a solution of 10R–7e (420 mg, 1.0 mmol) and 4-dimethyl-
aminopyridine (12 mg, 0.1 mmol) in pyridine (5 mL) was added
dropwise acetyl chloride (236 mg, 3 mmol). After stirring for 2 h at
rt, to the reaction mixture was added AcOEt (50 mL). The resulting
solution was washed with 3% HCl (3ꢂ25 mL) and satd aqueous NaCl

D. Minato et al. / Tetrahedron 65 (2009) 9742–9748
9747
(25 mL). The organic layer was dried over MgSO4 and the solvent
was removed under reduced pressure. The residue was subjected to
silica gel column chromatography (n-hexane/AcOEt¼3:1) to afford
9 in 75% yield.
silica gel column chromatography (n-hexane/AcOEt¼2: 1) to afford
12 as a single diastereomer in 73% yield.
4.9.1. 4R-Methoxy-3R-(10R-hydroxylethyl)-1-(10R-phenylethyl)-
azetidin-2-one (12). Colorless oil; 1H NMR (400 MHz, CDCl3)
d 1.27
4.6.1. Di-tert-butyl 3S-(10R-acetoxyethyl)-1-(10R-phenylethyl)azetidin-
(d, J¼6.4 Hz, 3H), 1.63 (d, J¼7.3 Hz, 3H), 1.80–2.50 (m, 1H), 2.99 (dd,
J¼3.6, 5.4 Hz, 1H), 3.24 (s, 3H), 4.08 (dq, J¼5.4, 6.4 Hz, 1H), 4.73 (d,
J¼1.0 Hz, 1H), 4.93 (q, J¼7.3 Hz, 1H), 7.26–7.36 (m, 5H); 13C NMR
27.4
2-one-4,4-dicarboxylate (9). White solid; mp 78–81 ꢀC; [
a
]
D
þ25.4
(c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
d 1.08 (s, 9H), 1.46 (d,
J¼6.6 Hz, 3H),1.53 (s, 9H),1.86 (d, J¼7.2 Hz, 3H), 2.03 (s, 3H), 4.01 (d,
J¼6.6 Hz,1H), 4.57 (q, J¼7.2 Hz,1H), 5.23 (q, J¼6.6 Hz,1H), 7.15–7.35
(m, 5H); IR (neat): 2980, 2934, 2380, 1769, 1740, 1495, 1456, 1395,
1456, 1395, 1341, 1244, 1159, 1144, 1115, 1065, 1048, 905, 849, 834,
760, 733, 700 cmꢁ1; Anal. Calcd for C25H35NO7: C, 65.06; H, 7.64; N,
3.03. Found: C, 64.95; H, 7.40; N, 2.90.
(100 MHz, CDCl3) d 19.4, 21.5, 51.4, 54.2, 62.7, 64.0, 84.5, 127.2, 127.7,
128.6, 139.8, 166.5; IR (neat): 3420, 3032, 2975, 2936, 2836, 1740,
1495, 1455, 1395, 1374, 1206, 1184, 1140, 1098, 1028, 997, 951, 864,
766, 700 cmꢁ1; HRMS calcd for C14H19NO3: 249.1365, found:
249.1354.
4.10. Silylation of 12
4.7. Preparation of dicarboxylic acid (10)
To a solution of 12 (60 mg, 0.24 mmol) and 4-dimethylamino-
pyridine (88 mg, 0.72 mmol) in N,N-dimethylformamide (1 mL)
was added tert-butyldimethylsilyl chloride (109 mg, 0.72 mmol).
After stirring for 24 h at rt, to the reaction mixture was added AcOEt
(30 mL). The resulting solution was washed with water (10 mL) and
satd aqueous NaCl (10 mL). The organic layer was dried over MgSO4
and the solvent was removed under reduced pressure. The residue
was subjected on silica gel column chromatography (n-hexane/
AcOEt¼5:1) to afford 13 in 65% yield.
To a solution of 9 (462 mg, 1.0 mmol) in dichloromethane (4 mL)
was slowly added trifluoroacetic acid (3.7 mL, 50 mmol). After
stirring for 2 h at rt, concentration of the reaction mixture under
reduced pressure afforded 10 in quantitative yield.
4.7.1. 3S-(10R-Acetoxyethyl)-1-(10R-phenylethyl)azetidin-2-one-4,4-
28.0
dicarboxylic acid (10). White solid; mp 132–136 ꢀC; [
a
]
D
þ25.3 (c
1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d
1.46 (d, J¼6.0 Hz, 3H), 1.83
(d, J¼7.2 Hz, 3H), 2.02 (s, 3H), 3.90 (d, J¼10.8 Hz, 1H), 4.63 (q,
J¼7.2 Hz, 1H), 5.45 (dq, J¼6.0, 10.8 Hz, 1H), 7.20–7.40 (m, 5H), 8.55
(m, 2H); IR (neat): 3500, 2984, 2359, 1750, 1541, 1497, 1456, 1375,
1260, 1180, 1160, 1063, 1050, 1028, 963, 912, 760, 700 cmꢁ1; HRMS
(EI) calcd for C17H19NO7 (Mþ): 349.1162, found: 349.1135.
4.10.1. 4R-Methoxy-3R-[10R-(tert-butyldimethylsilyloxy)ethyl]-1-
(10R-phenylethyl)azetidin-2-one (13). Colorless oil; 1H NMR
(400 MHz, CDCl3)
d
ꢁ0.02 (s, 3H), 0.02 (s, 3H), 0.80 (s, 9H), 1.21 (d,
J¼6.4 Hz, 3H), 1.63 (d, J¼7.3 Hz, 3H), 2.90 (dd, J¼0.6, 4.9 Hz, 1H),
3.20 (s, 3H), 4.05 (dq, J¼4.9, 6.4 Hz, 1H), 4.71 (d, J¼0.6 Hz, 1H), 4.86
(q, J¼7.3 Hz, 1H), 7.26–7.39 (m, 5H); 13C NMR (100 MHz, CDCl3)
4.8. Preparation of monocarboxylic acid (11)
d
ꢁ4.7, ꢁ4.7, 17.9, 20.0, 22.7, 25.7, 51.7, 54.1, 63.2, 64.4, 84.7, 127.3,
To a solution of 10 (349 mg, 1.0 mmol) in 2,4,6-collidine (2 mL)
was heated at 160 ꢀC with oil-bath. After heating for 1 h, to the
reaction mixture was added AcOEt (10 mL). The resulting carboxy-
late ion was collected with satd NaHCO3 (3ꢂ10 mL). Combined
aqueous layer was acidified with 5% HCl. The carboxylic acid was
extracted with AcOEt (3ꢂ20 mL). The resulting organic layer
washed with satd aqueous NaCl (25 mL). The organic layer was
dried over MgSO4 and the solvent was removed under reduced
pressure to afford 11 in quantitative yield.
127.6, 128.6, 139.9, 166.2; IR (neat): 3033, 2955, 2930, 2897, 2857,
1765, 1495, 1472, 1389, 1250, 1204, 1183, 1150, 1100, 1040, 1028,
1005, 934, 853, 812, 777, 700 cmꢁ1; HRMS (EI) calcd for C20H33NO3
(Mþ): 363.2230, found: 363.2199.
4.11. Removal of N-protecting group of 13
To anhydrous liq. ammonia (2 mL) was added Na (18 mg,
0.78 mmol) at ꢁ78 ꢀC. Successively, a solution of 13 (47 mg,
0.13 mmol) in tetrahydrofuran (2 mL) was added to the ammonia.
After stirring for 1 h at ꢁ78 ꢀC, to the reaction mixture was added
satd aqueous NaCl (10 mL). The organic portion was extracted with
AcOEt (3ꢂ10 mL). The resulting organic layer was washed with satd
aqueous NaCl (25 mL). The organic layer was dried over MgSO4 and
the solvent was removed under reduced pressure. The residue was
subjected to silica gel column chromatography (n-hexane/
AcOEt¼2:1) to afford 2a4 in 95% yield.
4.8.1. 3S-(10R-Acetoxyethyl)-1-(10R-phenylethyl)azetidin-2-one-4R-
carboxylic acid (11)(4R:4S¼72:28). White solid; mp 86–90 ꢀC; 1H
NMR (300 MHz, CDCl3)
d
1.30 (d, J¼6.3 Hz, 0.84H), 1.42 (d, J¼6.3 Hz,
2.16H), 1.60 (d, J¼6.9 Hz, 0.84H), 1.80 (d, J¼6.9 Hz, 2.16H), 1.89 (s,
0.84H), 1.95 (s, 2.16H), 3.26 (dd, J¼1.8, 10.5 Hz, 0.28H), 3.55 (dd,
J¼5.4, 10.5 Hz, 0.72H), 3.94 (d, J¼1.8 Hz, 0.28H), 4.07 (d, J¼5.4 Hz,
0.72H), 4.53 (q, J¼7.2 Hz, 0.72H), 5.57 (q, J¼7.2 Hz, 0.28H), 5.18–5.34
(m, 1H), 7.26–7.40 (m, 5H), 7.60–7.90 (m, 1H); IR (neat): 3500, 2982,
1748, 1638, 1541, 1497, 1456, 1379, 1242, 1200, 1142, 1050, 953, 924,
853, 799, 766, 722 cmꢁ1; HRMS (EI) calcd for C16H19NO5 (Mþ):
305.1263, found: 305.1277.
4.11.1. 4R-Methoxy-3R-[10R-(tert-butyldimethylsilyloxy)ethyl]zetidin-
27.0
2-one (2a). Colorless crystal; mp 56–58 ꢀC; [
a
]
D
ꢁ28.9 (c 1.4,
CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.07 (s, 3H), 0.08 (s, 3H), 0.87 (s,
4.9. Decarboxylative methoxylation of 11
9H), 1.26 (d, J¼6.4 Hz, 3H), 3.00 (dd, J¼1.0, 4.9 Hz, 1H), 3.37 (s, 3H),
4.17 (dq, J¼4.9, 6.4 Hz, 1H), 5.00 (d, J¼1.0 Hz, 1H), 6.53 (s, 1H); 13C
In an undivided cell equipped with platinum plate electrodes
(1ꢂ2 cm2) was placed a solution of 11 (101 mg, 0.33 mmol) and
NaOMe (54 mg, 1 mmol) in a mixture of acetonitrile (4 mL) and
methanol (1 mL). A constant current (50 mA) was passed through
the cell externally cooled with water-bath. After 2 F/mol of elec-
tricity was passed, to the reaction mixture was added AcOEt
(30 mL). The resulting solution was washed with satd aqueous NaCl
(10 mL). The organic layer was dried over MgSO4 and the solvent
was removed under reduced pressure. The residue was subjected to
NMR (100 MHz, CDCl3)
65.2, 81.5, 167.7.
d
ꢁ5.1, ꢁ4.3, 17.9, 22.5, 25.7, 25.7, 54.9, 64.2,
Acknowledgements
This work was supported by the JSPS Fellowships for Young
Scientists and by the president’s discretion fund of Nagasaki
University.

9748
D. Minato et al. / Tetrahedron 65 (2009) 9742–9748
Chem. Soc. 1990, 112, 2368–2372; (c) Shono, T.; Ishifune, M.; Okada, T.; Ka-
References and notes
shimura, S. J. Org. Chem. 1991, 56, 2–4; (d) Matsumura, Y.; Satoh, Y.; Shirai, K.;
Onomura, O.; Maki, T. J. Chem. Soc., Perkin Trans. 1 1999, 2057–2060.
1. A representative reviews, see: (a) Kametani, T.; Ihara, M. Yuki Gosei Kagaku
Kyokaishi 1980, 52, 1025–1036; (b) Nagahara, T.; Kametani, T. Heterocycles 1987,
25, 729–806; (c) Berks, A. H. Tetrahedron 1996, 52, 331–375.
8. Crystallographic data for structure of azetidin-2-one 7e have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 745174. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK; fax: þ44(0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk.
9. (a) Mori, M.; Kagechika, K.; Sasai, H.; Shibasaki, M. Tetrahedron 1991, 47, 531–
540; (b) Wanyoike, G. N.; Onomura, O.; Maki, T.; Matsumura, Y. Org. Lett. 2002,
4, 1875–1877; (c) Onomura, O.; Kirira, P. G.; Tanaka, T.; Tsukada, S.; Matsumura,
Y.; Demizu, Y. Tetrahedron 2008, 64, 7498–7503.
10. Although the corresponding 4-acetoxylated compound 14 was prepared
from 11 by electrochemical oxidation described below, the reduction of 14
with Na in liq. NH3 did not afford the corresponding N-unsubstituted aze-
tidin-2-one; see, electrochemical decarboxylative acetoxylation: In an un-
divided cell equipped with platinum plate electrodes (1ꢂ2 cm2) was placed
a solution of 11 (153 mg, 0.5 mmol) and AcOK (98 mg, 1 mmol) in a mixture
of acetonitrile (4 mL) and acetic acid (1 mL). A constant current (50 mA) was
passed through the cell externally cooled with water-bath. After 4 F/mol of
electricity was passed, to the reaction mixture was added satd NaHCO3
(30 mL). Organic portion was extracted with AcOEt (3ꢂ15 mL). The resulting
organic layer was washed with satd aqueous NaCl (10 mL). The organic layer
was dried over MgSO4 and the solvent was removed under reduced pres-
sure. The residue was subjected to silica gel column chromatography (n-
hexane:AcOEt¼2:1) to afford 14 in 60% yield. 4R-Acetoxy-3R-(10R-acetoxy-
ethyl)-1-(10R-phenylethyl)azetidin-2-one (14): colorless oil; 1H NMR (400 MHz
2. (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.;
Akutagawa, S.; Sayo, N.; Asito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem.
Soc. 1989, 111, 9134–9135; (b) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1990, 112, 7820–7822; (c) Kita,
Y.; Shibata, N.; Miki, T.; Takemura, Y.; Tamura, O. J. Chem. Soc., Chem. Commun.
1990, 727–729; (d) Nagao, Y.; Nagase, Y.; Kumagai, T.; Mastunaga, H.; Abe, T.;
Shimada, O.; Hayashi, T.; Inoue, Y. J. Org. Chem. 1992, 57, 4243–4249; (e) Lynch,
J. E.; Laswell, W. L.; Volante, R. P.; Reamer, R. A.; Tschaen, D. M.; Shinkai, I.
Heterocycles 1993, 35, 1029–1037; (f) Cozzi, F.; Annunziata, R.; Cinquini, M.;
Poletti, L.; Perboni, A.; Tamburini, B. Chirality 1998, 10, 91–94; (g) Cainelli, G.;
Galletti, P.; Giacomini, D. Tetrahedron Lett. 1998, 39, 7779–7782; (h) Tatsuta, K.;
Takahashi, M.; Tanaka, N.; Chikauchi, K. J. Antibiot. 2000, 53, 1231–1234; (i)
Laurent, M.; Ce´re´siat, M.; Marchand-Brynaert, J. J. Org. Chem. 2004, 69, 3194–
3197; (j) Laurent, M.; Ceresiat, M.; Marchand-Brynaert, J. Eur. J. Org. Chem. 2006,
3755–3766; (k) Singh, S. K.; Singh, G. B.; Byri, V. K.; Satish, B.; Dhamjewar, R.;
Gopalan, B. Synth. Commun. 2008, 38, 456–464; (l) Kuroboshi, M.; Miyada, M.;
Tateyama, S.; Tanaka, H. Heterocycles 2008, 76, 1471–1484.
3. Simig, G.; Doleschall, G.; Hornya´k, G.; Fetter, J.; Lempert, K.; Nyitrai, J.; Huszthy,
P.; Gizur, T.; Ka´jtar-Peredy, M. Tetrahedron 1985, 41, 479–484.
4. (a) Kita, Y.; Shibata, N.; Yoshida, N.; Tohjo, T. Chem. Pharm. Bull. 1992, 40, 1044–
1046; (b) Kita, Y.; Shibata, N.; Yoshida, N.; Kawano, M.; Matsumoto, K. J. Org.
Chem. 1994, 59, 938–939.
5. (a) Shiozaki, M.; Ishida, N.; Maruyama, H.; Hiraoka, T. Tetrahedron 1983, 39,
2399–2407; (b) Sa´nta, Z.; Pa´rka´nyi, L.; Ne´meth, I.; Nagy, J.; Nyitrai, J. Tetrahe-
dron: Asymmetry 2001, 12, 89–94.
6. (a) Carelli, I.; Insei, A.; Carelli, V.; Casadei, M. A.; Liberature, F.; Moracci, F. M.
Synthesis 1986, 591–593; (b) Casadei, M. A.; Rienzo, B. D.; Insei, A.; Moracci, F.
M. J. Chem. Soc., Perkin Trans. 11992, 379–382; (c) Feroci, M.; Chiarotto, I.; Orsini,
M.; Sotgiu, G.; Insei, A. Adv. Synth. Catal. 2008, 350, 1355–1359.
7. In this reaction "EGB" was not cleared yet but it might be the conjugated base of
3e. Representative literatures for electrochemical reactions using "EGB", see: (a)
Shono, T.; Kise, N.; Tanabe, T. J. Org. Chem. 1988, 53, 1364–1367; (b) Shono, T.;
Matsumura, Y.; Katoh, S.; Takeuchi, K.; Sasaki, K.; Kamada, T.; Shimizu, R. J. Am.
´
´
CDCl3)
d
1.24 (d, J¼6.3 Hz, 3H), 1.55 (d, J¼7.4 Hz, 3H), 1.83 (s, 3H), 1.90 (s, 3H), 3.09
(dd, J¼1.0 Hz, J¼5.8 Hz, 1H), 4.80 (q, J¼7.3 Hz, 1H), 5.09 (quint., J¼6.3 Hz, 1H), 5.92
(d, J¼1.0 Hz, 1H), 7.20–7.40 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 18.2, 19.1, 20.8,
20.8, 52.7, 62.3, 66.1, 78.0, 126.9, 127.9, 128.7, 140.1, 164.3, 169.9, 169.9; IR (neat):
3500, 2984, 2853, 1738, 1640, 1497, 1456, 1377, 1242, 1200, 1140, 1050, 953, 922,
851, 799, 722, 704 cmꢁ1; HRMS (EI) calcd for C17H21NO5 (Mþ): 319.1420, Found:
319.1430.
11. Battersby, A. R.; Turner, S. P. D.; Block, M. H.; Sheng, Z.-C.; Zimmerman, S. C. J. Chem.
Soc., Perkin Trans. 11988, 1577–1586.
12. Sugiyama, S.; Watanabe, S.; Inoue, T.; Kurihara, R.; Itou, T.; Ishi, K. Tetrahedron
2003, 59, 3417–3426.