On the regioselectivity for the Michael addition of thiols to unsymmetrical fumaric derivatives

Article abstract of DOI:10.1016/j.tet.2003.10.007

The regiochemistry of the Michael addition of thiols to unsymmetrical fumaric derivatives was investigated. Conjugate addition of thiols to unsymmetrical fumaric diester was well controlled by the presence of lithium cation and one of the two possible regioisomers was prepared in a highly selective manner. Fumaric ester amides underwent the regioselective Michael addition that was controlled by the presence or absence of the base; either of the regioisomers was prepared as an almost diastereomerically pure form. The present control of the regiochemistry can be explained by the factors of change of active site for the addition by the coordination or non-coordination of proton or lithium cation to the carbonyls. To clarify the origin of the regioselectivity, the relative rates of the conjugate addition of thiol to acrylate derivatives were measured under competitive conditions. Ethyl acrylate reacted with thiol faster than tert-butyl acrylate and the rate difference was enhanced by the presence of lithium cation. In the presence of base, ethyl acrylate gave the adducts much faster than acrylamide, while under non-basic conditions acrylamide showed higher reactivity than the ester. This regioselectivity was also observed in the Michael/aldol reaction and multi-substituted γ-butyrolactones were prepared in a stereoselective manner. The thio groups introduced here served as a leaving group and a convenient stereoselective synthesis of β-, γ- and δ-lactams was developed.

Full text of DOI:10.1016/j.tet.2003.10.007

Tetrahedron 59 (2003) 9537–9546
On the regioselectivity for the Michael addition of thiols
to unsymmetrical fumaric derivatives
a
a
a
a
Akio Kamimura,a Norikazu Murakami, Fukiko Kawahara, Kakuteru Yokota, Yoji Omata,
Kenji Matsuura,a Yusuke Oishi,a Rie Morita,a Hiromasa Mitsudera,a Hiroyuki Suzukawa,a
Akikazu Kakehi,b Masashi Shiraic and Hiroaki Okamotod
,
*
aDepartment of Applied Chemistry, Faculty of Engineering, Yamaguchi University, 2-16-1, Tokiwadai, Ube 755-8611, Japan
bDepartment of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Nagano 380-8553, Japan
cUbe Laboratory, Ube Industries Ltd., Ube 755-8633, Japan
dDepartment of Advanced Materials Science and Engineering, Faculty of Engineering, Yamaguchi University, Ube 755-8611, Japan
Received 17 September 2003; revised 3 October 2003; accepted 3 October 2003
Abstract—The regiochemistry of the Michael addition of thiols to unsymmetrical fumaric derivatives was investigated. Conjugate addition
of thiols to unsymmetrical fumaric diester was well controlled by the presence of lithium cation and one of the two possible regioisomers was
prepared in a highly selective manner. Fumaric ester amides underwent the regioselective Michael addition that was controlled by the
presence or absence of the base; either of the regioisomers was prepared as an almost diastereomerically pure form. The present control of the
regiochemistry can be explained by the factors of change of active site for the addition by the coordination or non-coordination of proton or
lithium cation to the carbonyls. To clarify the origin of the regioselectivity, the relative rates of the conjugate addition of thiol to acrylate
derivatives were measured under competitive conditions. Ethyl acrylate reacted with thiol faster than tert-butyl acrylate and the rate
difference was enhanced by the presence of lithium cation. In the presence of base, ethyl acrylate gave the adducts much faster than
acrylamide, while under non-basic conditions acrylamide showed higher reactivity than the ester. This regioselectivity was also observed in
the Michael/aldol reaction and multi-substituted g-butyrolactones were prepared in a stereoselective manner. The thio groups introduced
here served as a leaving group and a convenient stereoselective synthesis of b-, g- and d-lactams was developed.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
two regioisomers was formed in poor regioselectivity.2
Otherwise, conjugate adducts have been prepared in a
different way that involves several steps.3 In the previous
paper, we reported that the Michael addition of thiols to
unsymmetrical fumaric esters or amide esters was effec-
tively controlled and either of the regioisomers could be
prepared with good to high selectivity.4 In this paper we will
describe full details of the reaction as well as some
investigation on its mechanistic aspect. A synthetic
application that provides a useful method for the stereo-
selective preparation of b-, g- and d-lactams is also
performed.
Efficient control of selectivity during chemical transform-
ation has been of interest in organic chemistry. The Michael
addition is regarded as a useful reaction in organic
synthesis.1 Fumaric esters are used as an active C4 building
block due to the presence of two carboxylic groups that
enhance the reactivity of the carbon–carbon double bond
toward the Michael addition or other reactions. If the two
carboxylic groups are differently derivatized, however, they
incur a problem of regioselectivity. This may have been
recognized as a difficult problem to solve because their
steric and/or electronic differences, that should play a key
role for the control of regiochemistry, are very subtle and
provides insufficient control in a practical synthesis. As a
result, this simple but inherent problem has remained
unsolved so far. To the best of our knowledge, there has
been only one report on this issue, in which a mixture of the
Keywords: Michael addition; thiols; regioselectivity; lactams; radical
cyclization.
*
Corresponding author. Tel.: þ81-836-85-9231; fax: þ81-836-85-9201;
Scheme 1. Reagents and conditions: (i) RSH, base (0.1 equiv.), 2508C.
(ii) PhSSiMe3, TBAF (1 equiv.), 2508C.
e-mail: ak10@yamaguchi-u.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.007

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A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
Table 1. Regioselective Michael addition of thiols to unsymmetric fumaric esters
Entry
R1
R2
R
Time (h)
Conditions
2; Yield (%)a
A/Bb
1
2
3
4
5
6
7
8
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1.5
1.5
1.5
4.5
2.5
12
2
12
24
2.5
12
12
1.5
42
Et3N/C2H5CN
BuLi/THF
BuLi/CH2Cl2
Et3N/C2H5CN
Bu4NF/CH2Cl2
BuLi/THF
2a; 91 (7)
2a; 96 (3)
2a; 99 (0)
2b; 77 (2)
2b; 12 (–)d
2b; 75 (0)
2b; 82 (0)
2b; 84 (0)
2b;42 (42)
2c; 92 (0)
2d; 87 (0)
2e; 75 (0)
2f; 86 (0)
2g; 0 (100)
60/40
60/40
59/41
92/8
91/9
92/8
92/8
97/3
94/6
98/2
96/4
89/11
86/14
–
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
c
BuLi/DME
BuLi/CH2Cl2
BuLi/toluene
BuLi/CH2Cl2
BuLi/CH2Cl2
BuLi/CH2Cl2
BuLi/CH2Cl2
BuLi/CH2Cl2
9
10
11
12
13
14
o-MeC6H4–
p-MeC6H4–
Et
HOCH2CH2–
o-MeOC6H4–
Et
Et
Et
Et
a
Isolated yield. Recovery of the starting fumaric ester is in parentheses.
Determined by 1H NMR analyses.
PhSSiMe3 was used instead of PhSH.
Not determined.
b
c
d
2. Results and discussion
observed selectivity was in a similar level (entries 2 and 3).
To improve the regioselectivity, we examined the use of
ethyl tert-butyl fumarate. The conventional basic Michael
addition conditions brought the adduct 2b in about 92/8
selectivity, in which 2b-A was formed predominantly (entry
4). Other conditions such as PhSLi/PhSH and PhSSiMe3/
TBAF did not change the product ratio very much (entries
4–7). The A selectivity rose to 97/3 when CH2Cl2 was
employed as the reaction solvent (entry 8). Toluene also
worked as a useful solvent to achieve the high 2b-A
selectivity but the reaction rate decreased and the yield of 2b
was reduced to 42% (entry 9). Hence, we examined other
thiols for the Michael addition under the best reaction
conditions, PhSLi/PhSH/CH2Cl2.5 o-Thiocresol underwent
the highest selectivity 98/2 in the formation 2c (entry 10).6
Aliphatic thiol gave 2e and 2f in a less regioselective
manner (entries 12 and 13). o-Methoxythiophenol was quite
inert under these reaction conditions and no adduct was
formed (entry 14).
2.1. Regioselective Michael addition to unsymmetrical
fumaric diesters and amide esters
The Michael addition of thiophenol to unsymmetrical
fumaric diester 1 was examined (Scheme 1). The results
are summarized in Table 1.
Ethyl methyl fumarate underwent the Michael addition with
thiophenol to give the adduct 2a in 91% yield (entry 1). The
product, as we expected, contained the two regioisomers,
2a-A and 2a-B, in about 1:1 ratio so that the addition
occurred in non-selective manner. The use of lithium
thiolate as a base promoted the reaction smoothly, but the
The present procedure achieved the interesting high
regioselectivity in the Michael addition to unsymmetrical
fumaric diesters in which regioisomers 2-A were formed
predominantly. We were next interested in the regiocontrol
Scheme 2. Reagents and conditions: (i) PhSH, Et3N, C2H5CN. (ii) PhSH.
Table 2. Regioselective conjugate addition of thiols to fumaric amide ester 3
Entry
R1
R2
Conditionsa
4
Yield (%)b
A/Bc
1
2
3
4
5
6
7
8
–(CH2)4–
–(CH2)4–
–(CH2)5–
–(CH2)5–
X
Y
X
Y
X
Y
X
Y
X
Y
X
Y
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
88
89
87
80
46
91
61
88
77
20
93
70
10/90
.99/1
7/93
.98/2
13/87
.98/2
16/84
.98/2
2/98
83/17d
55/45
82/18
Bn
Bn
Bn
Bn
–CH2CHvCH2
–CH2CHvCH2
Bn
Bn
OBn
OBn
–CH2CHvCH2
–CH2CHvCH2
H
H
H
H
9
10
11
12
4f
a
X: Et3N (0.1 equiv.), C2H5CN, room temperature, 6 h; Y: no solvent, room temperature, 48 h.
Isolated yield.
Determined by HPLC or NMR analyses.
b
c
d
Before chromatographic purification. See Ref. 4.

A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
9539
of the Michael addition with fumaric amide ester 3
(Scheme 2). The results are summarized in Table 2.
alcohol 6 in a moderate yield.7 1H NMR indicated that the
a-protons at the ester groups in 6 appeared in ABX pattern
at 2.58 and 2.69 ppm which clearly supported the structure
of 6 shown in Scheme 3. Treatment of 5 with MeI in the
presence of DBU smoothly gave methyl ethyl ester, which
was identical to 2a-B.8
The presence of catalytic amount of Et3N prompted the
smooth Michael addition of 3a to form the adduct 4a in 88%
yield (entry 1). Obtained 4a consisted of two regioisomers
but regioisomer 4a-B predominated. Regioisomeric ratio
was found to be 10/90 so that the addition proceeded in a
good level of regioselectivity. To change or improve the
regioselectivity, we tried various reaction conditions. To our
surprise, the reaction occurred without an aid of base,
although the reaction time took 24 h until completion. The
product contained almost a single isomer that was found to
be 4a-A, the minor regioisomer obtained from the base-
catalyzed conditions (entry 2). Thus, the switching of the
orientation of the addition was now achieved by simple
choice of the reaction conditions. The use of other fumaric
amide ester also showed the same regiochemical behavior;
the base-catalyzed reaction gave 4-B selectively, while non-
basic conditions brought 4-A predominantly (entries 3–8).
The use of secondary amide ester also underwent smooth
formation of regioisomer B under the basic conditions, but
the formation of A under the non-basic conditions occurred
sluggishly (entries 9 and 10). The non-basic addition to
benzyloxyamide 3f took place smoothly to give 4f-A in
good yield, but the basic treatment of 3f afforded a mixture
of 4f-A and 4f-B.
Structure determination of the amide esters 4 was performed
in a similar manner. Treatment of 4a-A with LiBH4
achieved ester-selective reduction to give primary alcohol
1
7 in 49% yield. H NMR showed a-protons of the amide
group in 7 appeared at 2.65 and 2.73 ppm in ABX pattern so
that the structure of 7 was determined as Scheme 4 shows.
These results indicated the phenylthio group in 4a-A was
located in b-carbon to the amide group. Interestingly,
between regioisomers 4-A and 4-B there were apparent
difference in 1H NMR patterns that was very helpful for the
structural determination for other 4; in 4-B series, ABX
around 2–3 ppm always appeared separately with wider
gaps, i.e. the pair of signals was apart from each other, while
the corresponding gaps for 4-A series were narrower.
Additionally, in the series of regioisomer 4-A, the terminal
methyl group in the ethyl ester always appeared in up-field
than that in the regioisomer 4-B, although the reason
remained unclear. With help from these observations, we
determined all of the structures of 2 and 4.
2.2. Mechanistic investigation with competitive reaction
Structural elucidation was carried out by chemical trans-
formation of the adducts (Schemes 3 and 4). The adduct
2b-A, for example, was treated with TFA to give mono-
carboxylic acid 5, which was then reduced to terminal
The interesting results mentioned above fascinated us to
investigate the origin of the regioselectivity. First of all, we
examined the relative rates of the Michael addition of thiols
under various conditions (Scheme 5).
Scheme 3. Reagents and conditions: (i) TFA, thioanisole, room
temperature, 98%. (ii) BH3·THF, THF, 2108C to room temperature,
48%. (iii) Mel, DBU, toluene, room temperature, 74%.
Scheme 4. Reagents and conditions: (i) LiBH4, THF, 08C, 25 h, 49%.
Scheme 5.

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A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
The relative rate was measured with a competitive reaction.
The reaction was performed with a 1:1 mixture of the ethyl
and tert-butyl acrylates in the presence of 0.2 equiv. of
thiophenol and we measured the product ratio determined
by HPLC. The presence of Et3N gave a mixture of adducts 8
and 9 with the ratio in 4.4/1, whereas the ratio of 8/9 was
enhanced to 8.4/1 in the reaction catalyzed by PhSLi/PhSH.
Thus, ethyl acrylate is much reactive than tert-butyl acrylate
and the difference of the reactivity reached about twice as
much when the reaction performed in the presence of
lithium thiolate. These results suggest that the ethyl ester is
the much stronger activation group than the tert-butyl ester.
Thus, the ethyl ester side plays a key role in the
determination of the regiochemistry of the Michael
addition.
The base-catalyzed Michael addition of thiol to a mixture of
acrylic ester and acrylamide smoothly proceeded to give 8
predominantly. The ratio of 8/10 reached 8.6 that showed
acrylate was much reactive than acrylamide under basic
conditions. Non-basic reaction furnished the totally differ-
ent results. The mixture gave 10 as the main product and the
ratio between 8 and 10 became 0.19. Thus, the orientation of
the base-catalyzed Michael addition is governed by the ester
group, while the amide group acts as a main activating
group in the Michael addition without base.
Scheme 7.
The amide carbonyl, on the other hand, acts as a Lewis base
which coordinates to the acidic proton in thiophenol.10 This
activates the amide carbonyl group toward the nucleophilic
addition due to contribution of the iminium form through
equilibrium. The protonated amide group now becomes a
much stronger activating group than the ester.11 The
addition takes place from the b-carbon of the amide
selectively to give 4-A as a sole product. In the secondary
amide, however, sufficient formation of the iminium cation
should be prevented due to releasing NH-proton from the
iminium intermediates and the reaction rate under non-basic
conditions decreased. To confirm these hypotheses, we
executed the PM-3 level semi-empirical calculation for 3a
and 3a-Hþ (Scheme 8). In the optimized structure of 3a, the
coefficients of LUMO at C2 and C3 were 0.5400 and
20.5635, respectively, which indicated that C3, b-carbon of
the ester, is the reactive carbon under basic conditions.
When the amide carbonyl was protonated, the coefficients
were calculated to be 20.4703 for C2 and 0.1921 for C3, in
which C2, b-carbon of the amide, becomes much reactive
toward the nucleophilic attack. These calculation results
also support the observed regioselectivity for 3.
Scheme 6.
On the basis of these results, we assumed the reaction
mechanism as shown in Schemes 6 and 7. The regioselec-
tivity of the fumaric esters 1 is explained by the reactivity of
difference between ethyl ester and tert-butyl ester; 2b-A is
mainly formed because the ethyl ester acts as much reactive
group than tert-butyl ester group. The selectivity should be
enhanced by the presence of lithium cation in CH2Cl2 which
is expected to act as a Lewis acid.9 Lithium thiolate in
CH2Cl2 should prefer to coordinate with one of the ester
carbonyl groups and activate it. Due to steric hindrance
coming from tert-butyl group, coordination occurs more
easily to the ethyl ester group, which is activated and
encouraged nucleophilic attack of thiolate from its b-carbon
to give 2b-A selectively.
As the competitive reaction indicates, under basic Michael
addition conditions, the ester group in the amide ester 3
works as much stronger activating group than the amide so
thiolate anion attacks from the b-carbon of the ester group
preferentially (Scheme 7, upper). Absence of base, on the
other hand, causes the reaction rate to decrease. This is
probably because less amount of thiolate anion is generated.
Scheme 8.

A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
9541
2.3. Application of the regioselective addition to the
construction of heterocycles
The adducts of the present regioselective Michael addition
were regarded as potentially useful intermediates in organic
synthesis, because the sulfur group introduced in this
reaction was expected to work as a leaving group or an
activating group in the further molecular construction. So
we examined several reactions for the adducts.
Scheme 10. Reagents and conditions: (i) Mel, AgClO4, MeCN, room
temperature. (ii) K2CO3, acetone, reflux, 4 h 70%.
The use of the sulfur group as a radical precursor was
examined (Scheme 11).15 Treatment of 4d-B with Bu3SnH
induced in the 5-exo-trig mode radical cyclization and
2-pyrrolidone 17 was obtained in 69% yield. No simply
reduced product was observed. The diastereomeric ratio of
17 was about 5:1, in which trans-17 was found to be the
major isomer on the basis of NOE experiments. Compound
4d-A, on the other hand, underwent the radical cyclization
under slow-addition conditions, giving 16 in 68% yield.16
The slow-addition of Bu3SnH and AIBN was essential for
the efficient 6-exo-trig mode radical cyclization, otherwise
simple desulfurization dominated. To our surprise, 16
contained in a single isomer and the NOE experiment
indicated the stereochemistry in 16 was cis.17 No 7-endo
cyclized product was observed.18 Thus, this procedure
realized stereoselective formation of 2-pyrrolidone 17 and
2-piperidone 16 from the same starting material 3d in a two-
step procedure. Thus, this procedure will provide a useful
method for the preparation of these heterocyclic
compounds.
Application of the present procedure to the Michael/aldol
tandem reaction was examined (Scheme 9).12 A mixture of
lithium thiolate, benzaldehyde and unsymmetrical fumarate
1b gave a tandem adduct 11 in 83% yield. The adduct 11
contained four diastereomers which were all stereoisomers,
no regioisomer of 11 was found in the crude mixture.
Treatment of 11 with PPTS resulted in total recovery of the
starting material, which was in contrast to the smooth
formation of lactone 13 from the tandem adduct from
diethyl fumarate. The lactonization from 11 smoothly
occurred once the tert-butyl group was removed under
acidic conditions. Thus, the regioselectivity of the Michael
process was again achieved in a high level.
Scheme 9. Reagents and conditions: (i) PhSLi, PhChO, CH2Cl2, 2508C,
15 h, 83%. (ii) TFA, thioanisole, room temperature. (iii) PPTS, toluene,
1108C, 89% from 11 (4,5-cis/4,5-trans¼86/14). (iv) Ac2O, DMAP,
pyridine, room temperature, 2 h, 80% (dr¼89:11).
The ratio of the four diastereomers of 11 was determined
after their conversion to acetate 14, in which aldol ratio was
found to be anti/syn¼89/11. The ratio was close to the
diastereomeric ratio of lactone 13, 14/86.
Conversion to b-lactam was readily achieved from the
adduct from N-benzyloxyamides (Scheme 10). Treatment of
3f-A with MeI in the presence of AgClO4 resulted in the
smooth formation of sulfonium ion intermediate.13 Sub-
sequent exposure to K2CO3 provided b-lactam in 15 in 70%
yield.14
Scheme 11. Reagents and conditions: (i) Bu3SnH, AIBN, tolune, 1108C
slow addition (2 h), 68% (dr .98:2). (ii) Bu3SnH, AIBN, tolune, 1108C,
69% (dr¼5:1).

9542
A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
In conclusion, we have demonstrated a simple solution of
the control of Michael addition of thiols to unsymmetrical
fumaric derivatives. This control is very efficient and
desired regioisomers were prepared with high diastereo-
meric purity. The adduct serves as a useful intermediate for
efficient heterocyclic construction in regio- and stereo-
selective manner. Further the use of the reaction is now
underway in our laboratory.
4.14 (q, 2H, J¼7.2 Hz), 7.22–7.51 (m, 5H). 13C NMR
(67.5 MHz, CDCl3) d 13.6, 36.0, 45.3, 51.5, 61.0, 128.3,
128.7, 131.6, 133.7, 170.2, 170.6. Anal. calcd for
C13H16O4S: C, 58.19; H, 6.01. Found: C, 57.87; H, 6.00.
3.1.3. 2-Phenylthiosuccinic acid 4-ethyl ester 1-methyl
ester (2a-B). Oil. 1H NMR (270 MHz, CDCl3) d 1.23
(t, 3H, J¼7.3 Hz), 2.73 (dd, 1H, J¼5.6, 16.8 Hz), 2.95 (dd,
1H, J¼9.9, 16.8 Hz), 3.70 (s, 3H), 4.02 (dd, 1H, J¼5.6,
9.9 Hz), 4.13 (q, 2H, J¼7.3 Hz), 7.32–7.52 (m, 5H). 13C
NMR d (67.5 MHz, CDCl3) 13.9, 36.5, 45.5, 52.2, 60.7,
128.5, 128.9, 131.5, 133.9, 170.2, 171.3. Anal. calcd for
C13H16O4S: C, 58.19; H, 6.01. Found: C, 57.99; H, 6.00.
3. Experimental
3.1. General
3.1.4. 2-Phenylthiosuccinic acid 1-tert-butyl ester 4-ethyl
1
ester (2b-A). Oil. H NMR (270 MHz, CDCl3) d 1.33 (t,
All reactions were carried out under nitrogen atmosphere.
Purification of products were performed through flash
chromatography (silica gel/hexane or hexane–ether) if
necessary. Commercially available compounds except for
benzaldehyde were used without further purification.
Benzaldehyde was distilled under reduced pressure; it was
stored under nitrogen and used within a month after the
distillation. tert-Butyl ethyl fumarate, methyl ethyl fuma-
rate, and fumaric amide ester derivatives were prepared
from commercially available monoethyl fumaric ester. All
reaction solvents were dried over appropriate drying agents
3H, J¼7.1 Hz), 1.46 (s, 9H), 2.77 (dd, 1H, J¼5.6, 16.8 Hz),
2.99 (dd, 1H, J¼9.9, 17.2 Hz), 4.02 (dd, 1H, J¼5.6, 9.9 Hz),
4.23 (q, 2H, J¼7.3 Hz), 7.36–7.49 (m, 3H), 7.58–7.62 (m,
2H). 13C NMR (67.5 MHz, CDCl3) d 14.0, 27.6, 36.4, 46.3,
60.7, 81.5, 128.2, 128.7, 128.9, 133.6, 169.9, 170.4. Anal.
calcd for C16H22O4S: C, 61.91; H, 7.14. Found: C, 61.61; H,
7.32.
3.1.5. 2-p-Tolylthiosuccinic acid 1-tert-butyl ester 4-ethyl
1
ester (2d-A). Oil. H NMR (270 MHz, CDCl3) d 1.21 (t,
1
and distilled before use. H and 13C NMR spectra were
3H, J¼6.8 Hz), 1.40 (s, 9H), 2.34 (s, 3H), 2.65 (dd, 1H,
J¼5.6, 16.8 Hz), 2.85 (dd, 1H, J¼9.9, 16.7 Hz), 3.85 (dd,
1H, J¼5.6, 9.9 Hz), 4.13 (q, 2H, J¼6.9 Hz), 7.13 (d, 2H,
J¼7.9 Hz), 7.38 (d, 2H, J¼8.1 Hz). 13C NMR (67.5 MHz,
CDCl3) d 14.1, 21.1, 27.7, 36.5, 46.5, 60.8, 81.5, 128.3,
129.6, 134.4, 138.7, 170.1, 170.7. Anal. calcd for
C17H24O4S: C, 62.93; H, 7.46. Found: C, 62.39; H, 7.51.
recorded at 270 or 400 MHz and 67.5 or 100 MHz,
respectively. High resolution mass spectra (HRMS) were
measured at Advanced Instrumentation Centre, Ehime
University, Matsuyama, Japan.
3.1.1. Preparation of 2-o-tolylthiosuccinic acid 1-tert-
butyl ester 4-ethyl ester (2c-A). General procedure.
Under nitrogen atmosphere, BuLi in hexane (1.6 M,
0.0625 mL, 0.1 mmol) was added to a solution of o-thio-
cresol (128.7 mg, 1.04 mmol) in dry CH2Cl2 (10 mL,
distilled over CaH2) at 08C. The resulting solution was
cooled to 2508C and tert-butyl ethyl fumarate 1b
(193.7 mg, 0.967 mmol) was added. The reaction mixture
was allowed to stir at the same temperature for 4 h. The
reaction was quenched with addition of aqueous HCl (1 M,
30 mL) and the organic layer was separated. The water
phase was extracted with EtOAc (3£30 mL) and the
combined organic phase was dried over Na2SO4. After
filtration and evaporation, the crude product was purified
through flash chromatography (silica gel/hexane then
hexane–ether) to give 2c-A as oil in 92% yield
3.1.6. 2-Ethylthiosuccinic acid 1-tert-butyl ester 4-ethyl
ester (2e-A). Oil. 1H NMR (270 MHz, CDCl3) d 1.26 (t, 3H,
J¼7.2 Hz), 1.28 (t, 3H, J¼7.5 Hz), 1.48 (s, 9H), 2.61 (dd,
1H, J¼5.5, 16.8 Hz), 2.70 (qd, 2H, J¼7.4, 12.6 Hz), 2.92
(dd, 1H, J¼10.0, 16.8 Hz), 3.57 (dd, 1H, J¼5.6, 10.0 Hz),
4.15 (q, 2H, J¼7.2 Hz). 13C NMR (67.5 MHz, CDCl3) d
14.1, 14.4, 25.5, 27.8, 36.5, 42.2, 60.7, 81.4, 170.7, 170.8.
Anal. calcd for C12H22O4S: C, 54.93; H, 8.45. Found: C,
54.82; H, 8.63.
3.1.7. 2-(2-Hydroxyethylthio)succinic acid 1-tert-butyl
ester 4-ethyl ester (2f-A). Oil. 1H NMR (270 MHz, CDCl3)
d 1.27 (t, 3H, J¼7.1 Hz), 1.48 (s, 9H), 2.64 (dd, 1H, J¼6.9,
16.9 Hz), 2.79–3.01 (m, 4H), 3.64 (dd, 1H, J¼7.2, 8.5 Hz),
3.81 (t, 2H, J¼5.4 Hz), 4.17 (q, 2H, J¼7.1 Hz). 13C NMR
(67.5 MHz, CDCl3) d 14.0, 27.7, 35.0, 36.5, 42.3, 60.9,
61.0, 81.8, 170.7, 170.8. Anal. calcd for C12H22O5S: C,
51.78; H, 7.97. Found: C, 51.39; H, 8.04.
1
(289.5 mg). Minor isomer 2c-B could not be isolated. H
NMR (270 MHz, CDCl3) d 1.17 (t, 3H, J¼7.3 Hz), 1.27
(s, 9H), 2.39 (s, 3H), 2.61 (dd, 1H, J¼5.3, 16.9 Hz), 2.89
(dd, 1H, J¼9.9, 16.8 Hz), 3.87 (dd, 1H, J¼5.6, 10.2 Hz),
4.06 (q, 2H, J¼7.2 Hz), 7.07–7.15 (m, 2H), 7.45–7.47 (m,
2H). 13C NMR (67.5 MHz, CDCl3) d 14.0, 20.7, 27.5, 51.7,
36.4, 45.8, 61.0, 81.4, 126.2, 126.5, 127.1, 128.2, 128.4,
130.1, 131.9, 134.1, 140.8, 170.0, 170.4. Anal. calcd for
C17H24O4S: C, 62.93; H, 7.46. Found: C, 62.43; H, 7.68.
3.1.8. Michael addition to amide ester 3 under basic
conditions. Preparation of ethyl 4-oxo-3-phenylthio-4-(1-
pyrrolidinyl)butyrate (4a-B). General procedure. To a
solution of PhSH (550.9 mg, 5.0 mmol) and 3a (986.3 mg,
5.0 mmol) in C2H5CN (10 mL) was added Et3N (50.6 mg,
0.5 mmol) at room temperature and the reaction mixture
was allowed to stand for 6 h. dil HCl (10 mL) was added to
the reaction mixture and the resulting biphasic solution was
extracted with EtOAc (3£30 mL). Combined organic phase
was dried over Na2SO4. After filtration and evaporation of
Other compound 2 were prepared in a similar manner.
3.1.2. 2-Phenylthiosuccinic acid 1-ethyl ester 4-methyl
ester (2a-A). Oil. 1H NMR (270 MHz, CDCl3) d 1.20 (t, 3H,
J¼7.1 Hz), 2.73 (dd, 1H, J¼6.6, 17.2 Hz), 2.96 (dd, 1H,
J¼9.6, 16.7 Hz), 3.68 (s, 3H), 4.01 (dd, 1H, J¼6.6, 9.6 Hz),

A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
9543
solvent, crude product was purified through flash chroma-
tography (hexane–ethyl acetate 1:2 v/v) to give 4a-B in
88% yield (1.3487 g). Colorless oil. H NMR (270 MHz,
CDCl3) d 1.23 (t, 3H, J¼7.2 Hz), 1.80–1.90 (m, 4H), 2.65
(dd, 1H, J¼5.7, 17.1 Hz), 3.19 (dd, 1H, J¼10.0, 17.2 Hz),
3.37–3.55 (m, 4H), 4.05–4.14 (m, 3H), 7.30–7.51 (m, 5H).
13C NMR (67.5 MHz, CDCl3) d 14.0, 24.2, 25.9, 36.7, 44.7,
46.1, 46.3, 60.7, 128.6, 128.9, 129.2, 134.3, 167.9, 171.5.
Anal. calcd for C16H21NO3S: C, 62.51; H, 6.89; N, 4.56.
Found: C, 62.51; H, 6.78; N, 4.47.
3.1.13. N,N-Dibenzyl-3-phenylthiosuccinamic acid ethyl
ester (4c-B). Oil. 1H NMR (270 MHz, CDCl3) d 1.22,
(t, 3H, J¼7.3 Hz), 2.70 (dd, 1H, J¼4.6, 16.9 Hz), 3.24
(dd, 1H, J¼10.2, 17.2 Hz), 4.12 (q, 2H, J¼6.9 Hz), 4.27
(dd, 1H, J¼4.5, 10.2 Hz), 4.43 (d, 2H, J¼16.7 Hz), 4.93
(d, 1H, J¼17.1 Hz), 5.01 (d, 1H, J¼15.8 Hz), 7.20–7.51
(m, 15H). 13C NMR (67.5 MHz, CDCl3) d 14.1, 37.7, 42.9,
48.3, 50.2, 60.7, 127.1, 127.3, 127.4, 127.6, 128.4, 128.5,
128.6, 128.8, 129.0, 129.1, 134.1, 136.9, 169.9, 171.3. Anal.
calcd for C26H27NO3S: C, 72.03; H, 6.28; N, 3.23. Found:
C, 71.76; H, 6.27; N, 3.27.
1
3.1.9. Michael addition to amide ester 3 under non-basic
conditions. Preparation of ethyl 4-oxo-2-phenylthio-4-(1-
pyrrolidinyl)butyrate (4a-A). General procedure. A
mixture of PhSH (991.6 mg, 9.0 mmol) and 3a (1.188 g,
6.0 mmol) was allowed to stand at room temperature for
48 h. The mixture was directly subjected to flash chroma-
tography (hexane–ethyl acetate 1:2 v/v) to give 4a-A in
3.1.14. N,N-Diallyl-2-phenylthiosuccinamic acid ethyl
1
ester (4d-A). Oil. H NMR (270 MHz, CDCl3) d 1.16 (t,
3H, J¼7.3 Hz), 2.71 (dd, 1H, J¼4.6, 16.1 Hz), 3.03 (dd, 1H,
J¼10.2, 16.5 Hz), 3.84 (s, 2H), 3.95 (d, 2H, J¼5.5 Hz), 4.10
(dq, 2H, J¼3.6, 7.3 Hz), 4.17 (dd, 1H, J¼4.3, 10.2 Hz),
5.07–5.22 (m, 4H), 5.64–5.82 (m, 2H), 7.28–7.51 (m, 5H).
13C NMR (67.5 MHz, CDCl3) d 13.7, 35.3, 45.8, 47.8, 48.9,
60.9. 116.7, 117.1, 128.0, 128.7, 132.0, 132.4, 132.7, 133.2,
169.5, 171.5. Anal. calcd for C18H23NO3S: C, 64.84; H,
6.95; N, 4.20. Found: C, 64.67; H, 6.98; N, 4.00.
1
89% yield (1.6431 g). Colorless oil. H NMR (270 MHz,
CDCl3) d 1.16 (t, 3H, J¼7.0 Hz), 1.84 (m, 2H, J¼7.0 Hz),
1.92 (m, 2H, J¼7.3 Hz), 2.65 (dd, 1H, J¼4.8, 16.3 Hz), 2.95
(dd, 1H, J¼10.1, 16.3 Hz), 3.33–3.46 (m, 4H), 4.11 (q, 2H,
J¼6.8 Hz), 4.20 (dd, 1H, J¼4.2, 10.2 Hz), 7.15–7.52 (m,
5H). 13C NMR (67.5 MHz, CDCl3) d 13.9, 24.2, 25.9, 36.8,
45.6, 45.7, 46.3, 61.2, 128.1, 128.8, 132.6, 133.3, 168.1,
171.9. Anal. calcd for C16H21NO3S: C, 62.51; H, 6.89; N,
4.56. Found: C, 62.58; H, 6.83; N, 4.56.
3.1.15. N,N-Diallyl-3-phenylthiosuccinamic acid ethyl
1
ester (4d-B). Oil. H NMR (270 MHz, CDCl3) d 1.22 (t,
3H, J¼7.3 Hz), 2.67 (dd, 1H, J¼4.6, 16.2 Hz), 3.15 (dd, 1H,
J¼9.9, 16.4 Hz), 3.70 (dd, 1H, J¼6.3, 15.2 Hz), 3.88 (dd,
1H, J¼5.3, 17.6 Hz), 4.09 (q, 2H, J¼7.3 Hz), 4.18 (dd, 1H,
J¼4.6, 9.9 Hz), 4.22–4.35 (m, 2H), 5.14 (dd, 1H, J¼1.4,
17.5 Hz), 5.17 (dd, 1H, J¼1.3, 9.9 Hz), 5.24 (dd, 1H, J¼1.3,
10.9 Hz), 5.26 (dd, 1H, J¼1.3, 17.7 Hz), 5.66–5.92 (m,
2H), 7.31–7.47 (m, 5H). 13C NMR (67.5 MHz, CDCl3) d
13.9, 37.3, 42.5, 48.0, 49.3, 60.5, 117.1, 117.2, 128.6, 128.9,
132.7, 132.8, 134.0, 169.2, 171.2. Anal. calcd for
C18H23NO3S: C, 64.84; H, 6.95; N, 4.20. Found: C, 64.84;
H, 6.95; N, 4.13.
Other adducts 4 were prepared in a similar manner.
3.1.10. Ethyl 4-oxo-2-phenylthio-4-(1-piperidinyl)buty-
1
rate (4b-A). Oil. H NMR (270 MHz, CDCl3) d 1.16 (t,
3H, J¼7.0 Hz), 1.51–1.63 (m, 6H), 2.70 (dd, 1H, J¼4.3,
16.2 Hz), 3.02 (dd, 1H, J¼10.3, 16.2 Hz), 3.36–3.37
(m, 2H), 3.49–3.51 (m, 2H), 4.07–4.18 (m, 3H), 7.30–
7.54 (m, 5H). 13C NMR (67.5 MHz, CDCl3) d 13.6,
24.0, 25.1, 25.9, 35.2, 42.4, 45.8, 46.0, 60.7, 127.9, 128.6,
132.4, 133.0, 167.4, 171.6. Anal. calcd for C17H23NO3S:
C, 63.52; H, 7.21; N, 4.36. Found: C, 63.23; H, 7.24; N,
4.28.
3.1.16. N-Benzyl-3-phenylthiosuccinamic acid ethyl ester
1
(4e-B). Oil. H NMR (270 MHz, CDCl3) d 1.26 (t, 3H,
J¼7.1 Hz), 2.78 (dd, 1H, J¼6.6, 16.8 Hz), 3.13 (dd, 1H,
J¼7.3, 16.8 Hz), 4.04 (t, 1H, J¼6.9 Hz), 4.16 (q, 2H, J¼
7.2 Hz), 4.54 (dd, 2H, J¼3.6, 5.6 Hz), 6.75 (br, 1H), 7.18–
7.39 (m, 5H). 13C NMR (67.5 MHz, CDCl3) d 13.9, 36.5,
43.6, 47.6, 60.7, 127.2, 127.5, 128.0, 128.4, 129.1, 132.4,
132.5, 137.7, 169.7, 170.9. Anal. calcd for C19H21NO3S: C,
66.45; H, 6.16; N, 4.08. Found: C, 66.23; H, 6.17; N, 4.28.
3.1.11. Ethyl 4-oxo-3-phenylthio-4-(1-piperidinyl)buty-
rate (4b-B). Oil. 1H NMR (270 MHz, CDCl3) d 1.23 (t, 3H,
J¼6.9 Hz), 1.51–1.62 (m, 6H), 2.67 (dd, 1H, J¼4.9,
16.8 Hz), 3.15 (dd, 1H, J¼9.9, 16.8 Hz), 3.47–3.63 (m,
4H), 4.10 (dq, 2H, J¼3.7, 7.3 Hz), 4.30 (dd, 1H, J¼4.9,
9.9 Hz), 7.31–7.49 (m, 5H). 13C NMR (67.5 MHz, CDCl3)
d 13.9, 24.2, 25.3, 26.0, 37.0, 42.0, 43.2, 46.9, 60.4, 128.4,
128.8, 131.4, 133.9, 167.5, 171.2. Anal. calcd for
C17H23NO3S: C, 63.52; H, 7.21; N, 4.36. Found: C, 63.24;
H, 7.32; N, 4.11.
3.1.17. N-Benzyloxy-2-phenylthiosuccinamic acid ethyl
ester (4f-A). Oil. 1H NMR (270 MHz, DMSO-d6) d 1.07 (t,
3H, J¼7.3 Hz), 2.45 (dd, 1H, J¼6.4, 15.5 Hz), 2.58 (dd, 1H,
J¼8.6, 15.5 Hz), 3.97–4.08 (m, 3H), 4.76 (s, 2H), 7.35–
7.47 (m, 10H), 11.2 (br, 1H). 13C NMR (67.5 MHz, DMSO-
d6) d 13.9, 34.3, 45.5, 60.8, 77.0, 128.4, 128.5, 128.9, 129.2,
132.0, 133.2, 135.9, 166.2, 170.7. Anal. calcd for
C19H21NO4S: C, 63.49; H, 5.89; N, 3.90. Found: C, 63.10;
H, 6.07; N, 3.72.
3.1.12. N,N-Dibenzyl-2-phenylthiosuccinamic acid ethyl
ester (4c-A). Oil. 1H NMR (270 MHz, CDCl3) d 1.19 (t, 3H,
J¼7.3 Hz), 2.80 (dd, 1H, J¼4.6, 16.5 Hz), 3.15 (dd, 1H,
J¼10.5, 16.5 Hz), 4.15 (dq, 2H, J¼1.8, 7.3 Hz), 4.27 (dd,
1H, J¼4.8, 10.5 Hz), 4.41 (s, 2H), 4.52 (d, 1H, J¼14.9 Hz),
4.61 (d, 1H, J¼14.6 Hz), 4.14–4.48 (m, 15H). 13C NMR
(67.5 MHz, CDCl3) d 13.7, 35.7, 46.0, 48.2, 49.7, 61.2,
126.4, 127.3, 127.6, 128.0, 128.1, 128.4, 128.7, 128.8,
132.3, 134.1, 135.7, 136.6, 170.4, 171.6. Anal. calcd for
C26H27NO3S: C, 72.03; H, 6.28; N, 3.23. Found: C, 71.74;
H, 6.47; N, 3.16.
3.1.18. Preparation of 2-phenylthiosuccinic acid 4-ethyl
ester (5). 2b-A (0.2723 g, 0.8772 mmol) and thioanisole
(0.1 g) were added to trifluoroacetic acid (0.2 mL) and the
reaction mixture was allowed to stand for 1 h. Trifluoro-
acetic acid and thioanisole were removed in vacuo and 5
1
was obtained in 98% yield (0.219 g, 0.862 mmol). Oil. H

9544
A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
NMR (400 MHz, CDCl3) d 1.25 (t, 3H, J¼7.1 Hz), 2.75 (dd,
1H, J¼5.8, 17.0 Hz), 2.92 (dd, 1H, J¼9.4, 17.0 Hz), 4.01
(dd, 1H, J¼5.9, 9.6 Hz), 4.16 (q, 2H, J¼7.3 Hz), 7.26–7.53
(m, 5H), 10.68 (br, 1H). 13C NMR (67.5 MHz, CDCl3) d
14.4, 36.4, 36.9, 61.9, 129.2, 129.5, 131.5, 134.6, 171.4,
177.3. HRMS (FAB) calcd for (Mþ) C12H14O4S: 254.0613,
found 254.0620.
was combined and dried over Na2SO4. Crude product was
purified through flash chromatography (hexane–ethyl
1
acetate 5:1) to give 9 in 90% yield (214.9 mg). Oil. H
NMR (270 MHz, CDCl3) d 1.46 (s, 9H), 2.55 (t, 2H, J¼
7.3 Hz), 3.14 (t, 2H, J¼7.3 Hz), 7.21–7.52 (m, 5H).
Compounds 8 and 10 were prepared in a similar manner.
1
3.1.19. Preparation of ethyl 4-hydroxy-3-phenylthio-
butyrate (6). To a solution of 5 (0.2333 g, 0.9174 mmol)
in THF (10 mL) was added BH3·THF (1 M, 1.02 mL,
1.02 mmol) dropwise at 2108C and the reaction mixture
was allowed to stir at room temperature for 3.5 h. Aqueous
AcOH (50%, 5 mL) and THF were removed in vacuo.
NaHCO3 aq (50 mL) was added to the residue and the
resulting mixture was extracted with EtOAc (3£30 mL).
The organic phase was combined and dried over Na2SO4.
Chromatographic purification of crude product gave 6
in 48% yield (0.105 g, 0.4365 mmol). Oil. 1H NMR
(270 MHz, CDCl3) d 1.27 (t, 3H, J¼7.3 Hz), 2.40 (br,
1H), 2.58 (dd, 1H, J¼6.9, 16.2 Hz), 2.69 (dd, 1H, J¼6.8,
16.2 Hz), 3.58–3.67 (m, 3H), 4.16 (q, 2H, J¼7.1 Hz), 7.27–
7.36 (m, 3H), 7.45–7.50 (m, 2H). 13C NMR (67.5 MHz,
CDCl3) d 14.0, 36.6, 47.3, 60.7, 63.6, 127.7, 128.9, 132.5,
133.0, 171.4. HRMS (FAB) calcd for (MþH) C12H16O3S:
241.0899, found 241.0900.
3.1.23. Ethyl 3-phenylthiopropionate (8). Oil. H NMR
(270 MHz, CDCl3) d 1.25 (t, 3H, J¼7.3 Hz), 2.62 (t, 2H,
J¼7.2 Hz), 3.16 (t, 2H, J¼7.3 Hz), 4.14 (q, 2H, J¼6.9 Hz),
7.20–7.52 (m, 5H).
3.1.24. 3-Phenylthio-1-(1-pyrrolidinyl)-1-propanone
1
(10). Oil. H NMR (270 MHz, CDCl3) d 1.78–1.93 (m,
4H), 2.59 (t, 2H, J¼7.6 Hz), 3.23–3.35 (m, 4H), 3.45 (t, 2H,
J¼6.8 Hz), 7.17–7.52 (m, 5H).
3.1.25. Preparation of 2-(hydroxyphenylmethyl)-3-
phenylthiosuccinic acid 4-tert-butyl ester 1-ethyl ester
(11). BuLi (1.6 M, 4.1 mL, 6.5 mmol) was added to a
solution of PhSH (0.628 g, 5.5 mmol) in CH2Cl2 (10 mL) at
2508C. Then benzaldehyde (0.6369 g, 6.0 mmol) and
fumarate 1b (0.9984 g, 5.0 mmol) were added. The reaction
mixture was allowed to stir for 15 h at 2508C. dil HCl (1 M,
20 mL) was added to the reaction mixture and the resulting
biphasic mixture was extracted with EtOAc (3£30 mL). The
organic phase was combined and dried over Na2SO4. Crude
product was purified through flash chromatography
(hexane–ethyl acetate 5:1) to give 11 in 83% yield
(1.7193 g, 4.3 mmol). Anal. calcd for C23H28O5S: C,
66.32; H, 6.78. Found: C, 66.40; H, 6.55. Careful
chromatographic treatment separated the two major isomers
of 11, 11-A and 11-B.
3.1.20. Preparation of 2-phenylthiosuccinic acid 4-ethyl
ester 1-methyl ester (2a-B). To a solution of 6 (0.2463 g,
0.9685 mmol) in toluene (5 mL) was added DBU (0.1937 g,
1.27 mmol) and MeI (0.4798 g, 3.38 mmol) at room
temperature. The reaction mixture was allowed to stir for
20 h. Precipitate was filtered and the filtrate was concen-
trated in vacuo. The residue was diluted with CH2Cl2 and
the solution was washed with dil HCl and sat. NaHCO3.
Obtained crude product was purified through chroma-
tography to give 2a-B in 74% yield (0.1911 g, 0.712 mmol).
1
Compound 11-A. Oil. H NMR (270 MHz, CDCl3) d 0.93
(t, 3H, J¼6.9 Hz), 1.37 (s, 9H), 3.09 (ddd, 1H, J¼1.0, 3.6,
10.6 Hz), 3.06–3.12 (br, 1H), 3.91 (q, 2H, J¼6.9 Hz), 4.10
(d, 1H, J¼10.6 Hz), 5.53 (dd, 1H, J¼3.3, 7.3 Hz), 7.24–
7.34 (m, 8H), 7.52–7.56 (m, 2H). 13C NMR (67.5 MHz,
CDCl3) d 13.9, 28.0, 51.2, 53.8, 61.2, 71.5, 82.2, 125.6,
126.5, 127.8, 128.5, 129.3, 133.3, 133.5, 141.8, 170.3, 172.4.
3.1.21. Preparation of 4-hydroxy-3-phenylthio-1-(1-pyrro-
lidinyl)butan-1-one (7). To a solution of 4a-A (307.4 mg,
1.0 mmol) in THF (10 mL) was added LiBH4 (2 M in THF,
1.0 mL) at 08C and the reaction mixture was allowed to
stir at 08C for 25 h. Water (10 mL) was added and THF
was removed in vacuo. The resulting aqueous mixture was
extracted with CH2Cl2 (3£30 mL). The organic phase was
combined and dried over Na2SO4. Chromatographic
purification (hexane–ethyl acetate 4:1 v/v) of crude product
gave 7 in 49% yield (130.0 mg, 0.49 mmol). Colorless oil.
1H NMR (270 MHz, CDCl3) d 1.83–2.00 (m, 4H), 2.65 (dd,
1H, J¼7.6, 15.8 Hz), 2.73 (dd, 1H, J¼4.9, 15.8 Hz), 3.38 (q,
2H, J¼6.8 Hz), 3.48 (q, 2H, J¼6.9 Hz), 3.42–3.54 (br, 1H),
3.65–3.71 (m, 1H), 3.76–3.85 (m, 2H), 7.27-7.48 (m, 5H).
13C NMR (67.5 MHz, CDCl3) d 24.2, 25.9, 37.4, 45.8, 46.6,
46.7, 64.6, 127.2, 128.9, 132.0, 133.7, 169.5. HRMS (FAB)
calcd for (MþH) C14H20NO2S: 266.1215, found 266.1214.
Compound 11-B. Oil. 1H NMR (270 MHz, CDCl3) d 1.02 (t,
3H, J¼7.4 Hz), 1.40 (s, 9H), 3.35 (dd, 1H, J¼1.0, 3.6,
10.6 Hz), 3.63–3.73 (br, 1H), 4.02 (q, 2H, J¼7.3 Hz), 4.03
(d, 1H, J¼9.6 Hz), 5.00 (br, 1H), 7.25–7.61 (m, 10H). 13C
NMR (67.5 MHz, CDCl3) d 14.0, 27.9, 51.2, 54.2, 61.2,
72.6, 82.3, 125.4, 125.8, 128.4, 128.9, 129.0, 129.6, 133.4,
141.5, 169.6, 172.2.
3.1.26. Preparation of 3-ethoxycarbonyl-5-oxo-2-phenyl-
4-phenylthiotetrahydrofuran (13). A solution of 11
(0.4429 g, 1.06 mmol) and thioanisole (0.1 g) in trifluoro-
acetic acid (0.2 mL) was allowed to stand at room
temperature for 1 h. Trifluoroacetic acid and thioanisole
were removed in vacuo. The residue was solved in toluene
(10 mL) in the presence of PPTS (0.1 g) and the resulting
solution was heated under refluxing conditions for 1 h.
Solvent was removed in vacuo and the residue was
subjected to flash chromatography (hexane–ethyl acetate
5:1) to give 13 in 89% yield (0.3255 g). The ratio of he
four isomers was A–B–C–D¼59:27:9:5. Anal. calcd for
3.1.22. Preparation of tert-butyl 3-phenylthiopropionate
(9). A mixture of PhSH (110.1 mg, 1.0 mmol), tert-butyl
acrylate (128.2 mg, 1.0 mmol) and Et3N (13.9 mL,
0.1 mmol) in C2H5CN (5 mL) was allowed to stand at
room temperature for 24 h. dil HCl (1 M, 20 mL) was added
to the reaction mixture and the resulting biphasic mixture
was extracted with EtOAc (3£30 mL). The organic phase

A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
9545
C19H18O4S: C, 66.65; H, 5.30. Found: C, 66.66; H, 5.30.
Further chromatographic separation gave two major isomers
13-A and 13-B, both of which contain 4,5-cis-configuration,
in pure form. Configuration of 13-B was determined X-ray
crystallographic analysis.19
ture. The resulting mixture was heated at refluxing
temperature for 4 h. The reaction mixture was filtered and
water (30 mL) was added to the filtrate. Acetone was
removed in vacuo and the residue was extracted CH2Cl2
(3£30 mL). The organic phase was combined and dried over
Na2SO4. After filtration and evaporation of solvent, crude
product was purified through flash chromatography
(hexane–ethyl acetate 4:1 v/v) to give 15 in 70% yield
(173.2 mg). Oil. 1H NMR (270 MHz, CDCl3) d 1.30 (t, 3H,
J¼7.3 Hz), 2.76 (dd, 1H, J¼2.8, 13.5 Hz), 2.93 (dd, 1H,
J¼6.0, 13.8 Hz), 4.10 (dd, 1H, J¼2.6, 5.9 Hz), 4.22 (q, 2H,
J¼6.9 Hz), 5.01 (d, 1H, J¼11.2 Hz), 5.08 (d, 1H, J¼
11.2 Hz), 7.36–7.42 (m, 5H). 13C NMR (67.5 MHz, CDCl3)
d 13.9, 37.1, 56.8, 61.8, 78.5, 128.5, 128.8, 128.9, 134.9,
163.6, 169.1. HRMS (FAB) calcd for (MþH) C13H16NO4:
250.1079, found 250.1086.
Compound 13-A. Mp 1088C; 1H NMR (400 MHz, CDCl3) d
0.95 (t, 3H, J¼7.1 Hz), 3.84–3.91 (m, 3H), 4.29 (d, 1H,
J¼7.3 Hz), 5.60 (d, 1H, J¼5.7 Hz), 7.30–7.38 (m, 8H),
7.56–7.59 (m, 2H). 13C NMR (100 MHz, CDCl3) d 13.7,
52.5, 54.4, 61.3, 78.9, 125.2, 128.5, 128.7, 129.4, 132.8,
134.0, 134.4, 167.5, 172.5.
Compound 13-B. Mp 117–1188C; 1H NMR (400 MHz,
CDCl3) d 0.84 (t, 3H, J¼7.2 Hz), 3.62–3.67 (m, 2H), 3.76
(qd, 1H, J¼7.2, 10.8 Hz), 4.35 (d, 1H, J¼5.6 Hz), 5.55
(d, 1H, J¼8.0 Hz) 7.18–7.20 (m, 2H), 7.30–7.33 (m, 3H),
7.36–7.39 (m, 3H), 7.61–7.64 (m, 2H). 13C NMR
(100 MHz, CDCl3) d 13.5, 47.4, 53.6, 61.5, 79.4, 125.6,
128.5, 129.0, 129.4, 129.5, 130.6, 134.4, 134.8, 168.3,
173.1.
3.1.29. Preparation of 1-allyl-4-ethoxycarbonyl-5-
methyl-2-oxopiperidine (16). To a solution of 4d-A
(333.5 mg, 1.0 mmol) in toluene (30 mL) at 1108C was
added a solution of Bu3SnH (436.6 mg, (1.5 mmol) and
AIBN (34.0 mg, 0.2 mmol) in toluene (20 mL) over 2 h.
The reaction mixture was heated for additional 4 h. Toluene
was removed in vacuo and the residue was subjected to flash
chromatography (hexane–ethyl acetate 5:1 then 1:1 v/v) to
3.1.27. Preparation of 2-(acetoxyphenylmethyl)-3-
phenylthiosuccinic acid 4-tert-butyl ester 1-ethyl ester
(14). Acetic anhydride (0.5 mL, 0.55 mmol) was added to a
solution of 11 (0.205 g, 0.493 mmol) in pyridine (10 mL).
DMAP (0.1 g) was added and the resulting solution was
allowed to stand at room temperature for 2 h. The reaction
mixture was poured into ice–water (10 mL) and extracted
with MTBE (3£30 mL). The organic phase was combined
and dried over Na2SO4. Crude product was purified
through flash chromatography (hexane–ethyl acetate 10:1
then 3:1) to give 14 in 80% yield (0.1799 g). The ratio of
the four isomers was A–B–C–D¼66:23:6:5. HRMS
(FAB) calcd for (MþH) C25H31O6S: 459.1841, found
459.1844.
1
give 16 in 68% yield (155.5 mg). Oil. H NMR (270 MHz,
CDCl3) d 1.03 (d, 3H, J¼6.9 Hz), 1.27 (t, 3H, J¼7.3 Hz),
2.37–2.45 (m, 1H), 2.54 (dd, 1H, J¼6.6, 17.8 Hz), 2.69 (dd,
1H, J¼6.9, 17.8 Hz), 2.88 (dt, 1H, J¼3.9, 6.9 Hz), 3.10 (dd,
1H, J¼6.6, 12.2 Hz), 3.31 (dd, 1H, J¼4.6, 12.2 Hz), 3.86
(dd, 1H, J¼6.8, 14.9 Hz), 4.13 (dd, 1H, J¼6.0, 14.9 Hz),
4.17 (q, 2H, J¼6.9 Hz), 5.17 (d, 1H, J¼11.2 Hz), 5.18 (d,
1H, J¼15.7 Hz), 5.68–5.82 (m, 1H). 13C NMR (67.5 MHz,
CDCl3) d 14.1, 14.4, 29.5, 31.7, 42.4, 49.2, 51.7, 60.6,
117.4, 132.4, 167.6, 172.3. HRMS (FAB) calcd for (MþH)
C12H20NO3: 226.1443, found 226.1445.
1
Compound 14-A. Oil. H NMR (270 MHz, CDCl3) d 1.01
3.1.30. Preparation of ethyl 1-allyl-4-methyl-2-oxo-
pyrrolidin-3-acetate (17). A solution of 4d-B (333.5 mg,
1.0 mmol), Bu3SnH (436.6 mg (1.5 mmol) and AIBN
(36.5 mg, 0.2 mmol) in toluene (10 mL) was heated at
1108C for 2 h. Toluene was removed in vacuo and the
residue was subjected to flash chromatography (hexane–
ethyl acetate 5:1 then 1:1 v/v) to give 17 in 69% yield
(155.1 mg). Oil. 1H NMR (270 MHz, CDCl3) d 1.14 (d, 3H,
J¼6.6 Hz), 1.27 (t, 3H, J¼7.0 Hz), 2.12–2.23 (m, 1H), 2.46
(d, 1H, J¼11.5 Hz), 2.47 (m, 1H), 2.79 (d, 1H, J¼11.5 Hz),
2.90 (dd, 1H, J¼8.2, 9.5 Hz), 3.39 (dd, 1H, J¼7.9, 9.5 Hz),
3.85 (dd, 1H, J¼7.6, 15.2 Hz), 3.92 (dd, 1H, J¼7.2,
15.2 Hz), 4.16 (q, 2H, J¼6.9 Hz), 5.18 (dd, 1H, J¼1.3,
12.5 Hz), 5.19 (dd, J¼1.3, 17.5 Hz). 13C NMR (67.5 MHz,
CDCl3) d 14.1, 18.0, 33.5, 34.5, 45.2, 46.3, 52.2, 60.5,
117.8, 132.3, 172.0, 174.6. Anal. calcd for C12H19NO3: C,
63.98; H, 8.50; N, 6.22. Found: C, 64.17; H, 8.59; N,
6.14.
(t, 3H, J¼7.3 Hz), 1.41 (s, 9H), 2.00 (s, 3H), 3.15 (dd, 1H,
J¼4.3, 10.6 Hz), 3.89 (d, 1H, J¼10.6 Hz), 3.91 (q, 1H, J¼
7.3 Hz), 3.98 (q, 1H, J¼7.3 Hz), 6.55 (d, 1H, J¼4.3 Hz),
7.18–7.34 (m, 8H), 7.50–7.53 (m, 2H). 13C NMR
(67.5 MHz, CDCl3) d 13.7, 20.7, 27.7, 50.9, 52.9, 60.7,
72.6, 82.0, 125.8, 127.9, 128.3, 129.0, 133.4, 138.4, 169.4,
169.8, 170.0.
1
Compound 14-B. Oil. H NMR (270 MHz, CDCl3) d 1.11
(t, 3H, J¼7.3 Hz), 1.34 (s, 9H), 2.08 (s, 3H), 3.41 (dd, 1H,
J¼6.6, 9.5 Hz), 3.71 (d, 1H, J¼9.2 Hz), 3.87–4.13 (m, 2H),
6.11 (d, 1H, J¼6.3 Hz), 7.12–7.56 (m, 10H). 13C NMR
(67.5 MHz, CDCl3) d 13.8, 20.7, 27.8, 51.0, 52.6, 60.8,
72.7, 82.2, 125.8, 127.9, 128.1, 128.3, 128.4, 133.1, 137.4,
168.9, 169.3, 169.4.
3.1.28. Preparation of 2-ethoxycarbonyl-1-benzyloxy-2-
azetidinone (15).14 To a solution of 4f-A (359.4 mg,
1.0 mmol) and MeI (1.419 g, 10 mmol) in CH3CN
(12 mL) was added AgClO4 (1.037 g, 5.0 mmol) at room
temperature and the resulting mixture was allowed to stir for
17 h. Precipitate was filtered and solvent of the filtrate was
removed in vacuo. The residue was solved in acetone
(20 mL) and the solution was added to a mixture of K2CO3
(1.244 g, 9.0 mmol) in acetone (20 mL) at room tempera-
Acknowledgements
The present work was partially supported by the Grant-in-
Aid (11640536) from the Ministry of Education, Science
and Culture, Japan.

9546
A. Kamimura et al. / Tetrahedron 59 (2003) 9537–9546
Nishimura, K.; Nagaoka, Y.; Tomioka, K. Tetrahedron Lett.
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