Catalytic Asymmetric Conjugate Addition and Sulfenylation of Diarylthiazolidin-2,4-diones

Article abstract of DOI:10.1021/acs.joc.6b01637

This work reports the first application of diarylthiazolidin-2,4-diones as nucleophiles in asymmetric catalysis. By utilizing chiral amino acid-based (thio)urea-tertiary amines as the catalysts, we successively established asymmetric conjugate addition to nitroolefins and sulfenylation to N-(sulfanyl)-succinimides of diarylthiazolidin-2,4-diones. Two series of biologically important 5-aryl-5-substituted thiazolidin-2,4-diones were obtained with high enantio- and diastereoselectivities (up to >99% ee and >19:1 dr). The enantioenriched adducts were found to show satisfactory anticancer activities against three different cancer cell lines using the MTT assay. All of these successes depended on the development of a general and expedient synthetic strategy to provide diverse 5H-thiazolidin-2,4-diones.

Full text of DOI:10.1021/acs.joc.6b01637

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Article
Catalytic Asymmetric Conjugate Addition and
Sulfenylation of Diarylthiazolidin-2,4-Diones
Lihui Jiao, Liwei Bu, Xinyi Ye, Xiaowei Zhao, and Zhiyong Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01637 • Publication Date (Web): 23 Sep 2016
Downloaded from http://pubs.acs.org on September 24, 2016
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Catalytic Asymmetric Conjugate Addition and Sulfenylation of
Diarylthiazolidin-2,4-Diones
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Lihui Jiao,†,¶ Liwei Bu,†,¶ Xinyi Ye,‡ Xiaowei Zhao,† and Zhiyong Jiang*,†
†Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University,
Kaifeng, Henan, P. R. China, 475004
‡Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link,
637371, Singapore
E-mail: chmjzy@henu.edu.cn
Abstract:
This work reports the first application of diarylthiazolidin-2,4-diones as nucleophiles in
asymmetric catalysis. By utilizing chiral amino acid-based (thio)urea−tertiary amines as the
catalysts, asymmetric conjugate addition to nitroolefins and sulfenylation to
N-(sulfanyl)-succinimides of diarylthiazolidin-2,4-diones have been established successively.
Two series of biologically important 5-aryl-5-substituted thiazolidin-2,4-diones were obtained
in high enantio- and diastereoselectivities (up to >99% ee and >19:1 dr). The enantio-enriched
adducts were found to show satisfactory anticancer activities against three different cancer
cell lines using the MTT assay. All the successes depended on the development of a general
and expedient synthetic strategy to provide diverse 5H-thiazolidin-2,4-diones.
Keywords: Asymmetric organocatalysis; Thiazolidinediones; Diarylthiazolidin-2,4-diones;
Conjugate addition; Sulfenylation
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INTRODUCTION
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Thiazolidinediones1, also known as glitazones2 are important heterocyclic compounds for the
treatment of type II diabetes mellitus. More complex compounds such as 5-aryl-5-substituted
thiazolidin-2,4-diones bearing a fully substituted stereogenic center on the 5-position are also
important as they are promising drug candidates as inhibitors of lactamase3a and aldose
reductase,3b agrochemical fungicides3c and angiotensin-II receptor antagonists3d (compounds
I-IV, Figure 1). To our knowledge, the asymmetric synthesis of chiral 5-aryl-5-substituted
thiazolidin-2,4-diones has not been established yet.
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O
O
O
N
N
H
N
HN
NH
HN
N
N
S
O
S
O
S
H2NO2S
O
PhO
N
II: aldose reductase
I: lactamase inhibitor
III: agrochemical fungicide
inhibitor
H
O
N
O
N
N
S
N
IV: angiotensin-II receptor
N
antagonist
Figure 1. Representative examples of bioactive compounds.
Structurally, catalytic asymmetric reaction using the enolizable 5-aryl-substituted
thiazolidin-2,4-diones as nucleophiles would provide the most direct approach to the desired
chiral 5-aryl-5-substituted thiazolidin-2,4-diones. Wheeler᾽s synthetic method of making
diarylthiazolidin-2,4-diones (N-aryl-5-aryl-substituted thiazolidin-2,4-diones) could be dated
back to more than a century ago.4 From then on, no reports of these heterocyclic molecules in
catalytic reaction were further pursued.5 In this context, the development of asymmetric
reaction using diarylthiazolidin-2,4-diones as reagents remains highly desirable and
challenging, given their less known chemical reactivity.
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In recent years, we have invested great efforts in developing organocatalytic asymmetric
strategies to access biologically important chiral molecules with hetero-quaternary (thia6 and
oxa7) stereogenic centers. As an extension of these works, we herein report the first catalytic
asymmetric reaction of diarylthiazolidin-2,4-diones, including conjugate addition to
nitroolefins and sulfenylation to N-(sulfanyl)-succinimides, thus leading to the desired chiral
5-aryl-5-substituted thiazolidin-2,4-diones with high stereoselectivity. To this end, a general
and efficient synthetic method of 5H-thiazolidin-2,4-diones is reported for the first time.
RESULTS AND DISCUSSION
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Reported synthetic protocols4,8 for 5-aryl-substituted thiazolidin-2,4-diones lack the product
scope thus re-igniting our interest in this work. As shown in Scheme 1, the representative
diphenylthiazolidin-2,4-dione 5a could be prepared from commercially available phenylacetic
acid 1a through a simple three-step process. Treatment of AIBN and NBS could transform 1a
to α-bromo carboxylic acid 2a in 95% yield. Subsequently 2a was condensed with diphenyl
thiourea 3a in the presence of NaOAc to form 2-(phenylimino)-4-thiazolidinone 4a in 71%
yield. After hydrolysis with HCl, diphenylthiazolidin-2,4-dione 5a was obtained satisfactorily.
Noteworthy is that this methodology is versatile and suitable to provide a series of
5H-thiazolidin-2,4-diones with diverse N-functionalized groups and 5-aryl, benzyl and alkyl
substituents (5b-m).9
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Scheme 1. Representative synthesis of 5H-thiazolin-2,4-diones.
Figure 2. Structures of catalysts A−G.
To explore the reactivity of 5H-thiazolidin-2,4-diones, we first attempted catalytic
asymmetric conjugate addition to the most commonly used electrophiles, i.e. nitroolefins. The
reaction between diphenylthiazolidin-2,4-dione 5a and nitroolefin 6a was chosen as the
model reaction (Table 1). Our recent works have revealed that L-amino acid-based
urea−tertiary amines as efficient bifunctional Brønsted base catalysts could be conveniently
prepared.7d-f Therefore, L-tert-leucine-based urea−tertiary amine A (Figure 2) was first
screened as the catalyst (entry 1). It was found that the reaction worked smoothly in toluene at
o
25 C, and the desired conjugate adduct 7a was obtained in 77% yield after 24 hours. While
enantio- and diastereoselectivity were poor, the good reactivity encouraged us to further
examine the asymmetric reaction with catalysts B and C, containing pyrrolidine and
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diethylamine as the tertiary amine moiety respectively (entries 2−3). Catalysts B and C did
not give improved results. Next, we examined catalyst D with L-threonine as the chiral
skeleton and tert-butyldimethylsilyl (TBDMS) as the alcohol protecting group, and ee value
of 7a was increased to 30% (entry 4). We also observed that the analogous thiourea E slightly
improved the enantioselectivity, but the reaction became sluggish (Table 1, entry 5). Effect of
the substituent of urea was then investigated (catalysts F and G, entries 6−7). It was detected
that catalyst G with a 4-PhO-Ph urea moiety could further increase the enantioselectivity
(entry 7), indicating that different substituents of urea affected the H-bond interactions
between urea and the substrate (see Figure 3) thus leading to distinct stereoselective
outcomes.
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Table 1. Screening Studiesa
yield
entry cat. solvent t (h)
ee (%)c
drc
(%)b
77
49
81
62
27
73
71
76
87
82
85
89
64
91
89
92
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14d
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16f
A
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D
E
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
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24
24
24
18/6
15/4
17/4
30/12 52:48
32/13 46:54
32/13 52:48
36/27 53:47
23/17 51:49
27/8
35/15 48:52
60/9
77/7
81/1
48:52
57:43
47:53
F
G
G
G
G
G
G
G
G
G
G
Et2O
CH2Cl2
54:46
m-xylene 24
m-xylene 48
m-xylene 48
m-xylene 60
m-xylene 60
m-xylene 60
64:36
78:22
82:18
87/11 83:17
84/9
89/4
86:14
90:10
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aThe reaction was carried out with 0.05 mmol of 5a, 0.06 mmol of 6a, and 0.005 mmol of
catalyst in 0.5 mL solvent. Entries 1−11, T = 25 oC; entry 12, T = 0 oC; entries 13−16, T = −20
7
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c
d
oC. Isolated yield. Determined by HPLC methods. 25 mg of 4 Å molecular sieves were
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used. NaCl (10 mol%) was used. Both 25 mg of 4 Å molecular sieves and 10 mol% NaCl
were utilized.
In the presence of 10 mol% of catalyst G, a range of solvents, including THF, ether,
dichloromethane and m-xylene, were evaluated (Table 1, entries 8−11), and m-xylene was the
best, providing 7a in 85% yield with 60% ee and 64:36 dr (entry 11). When the temperature
was decreased, both enantio- and diastereoselectivity were improved (Table 1, entries 12−13);
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at −20 C, 7a with 81% ee and 82:18 dr was attained (entry 13). The effect of additive was
examined (entries 14−16). Molecular sieves (4 Å; 10 mg) boosted the enantioselectivity but
gave similar diastereoselectivity (entry 14).7b NaCl was shown to be effective in enhancing
diastereoselectivity (entry 15). The combination of 4 Å molecular sieves and NaCl optimally
provided 7a in 92% yield with 89% ee and 90:10 dr (entry 16).
Subsequently, we anticipated to improve the stereoselectivity by modifying the
N-substituent from N-phenyl of 5a to other aryl groups. As shown in Table 2, the introduction
of 4-MePh (5b) and 4-ClPh (5c) on the N-position led to similar enantio- and
diastereoselectivities (Table 2, entries 1−2). Surprisingly, no reaction was observed for 5d
(3-ClPh) (entry 3). The best results were obtained with 4-MeOPh (5e) substituent on the
N-position, and the corresponding product 7f was attained in 90% yield with 98% ee and
90:10 dr (entry 5). These results indicated that the N-substituted aryl groups are pivotal for
modulating the reactivity and stereoselectivity.
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Table 2. Investigation on the effect of N-aryl groups of 5a
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entry
5
7
yield (%)b ee (%)c
drc
92:8
87:13
N.A.
90:10
90:10
1
2
3
4
5
5b 7b
5c 7c
5d 7d
5e 7e
5f 7f
87
83
87
85
N.R.
71
N.A.
87
90
98
aThe reaction was carried out with 0.05 mmol of 5, 0.06 mmol of 6a, 0.005 mmol of
catalyst G, 0.005 mmol of NaCl and 25 mg of 4 Å molecular sieves in 0.5 mL m-xylene.
bIsolated yield. cDetermined by HPLC methods. N.R. = no reaction.
With the optimized reaction conditions in hand, the reaction scope was expanded (Table 3).
First, we evaluated the conjugate addition of 5e with a variety of nitroolefins 6 in the presence
o
of 10 mol% of catalyst G at −20 C in m-xylene solvent and employing 4Å molecular sieves
and NaCl as additives (Table 3, entries 1−12). The corresponding conjugate adducts 7f−q
were obtained in 63−97% yield with 74% to 99% ee and 5:1 to >19:1 dr within 72−96 hours.
2-Thienyl nitroolefin (7p, Table 3, entry 11) was found to suppress enantioselectivity. With 15
mol% of catalyst G, enantiomeric pure adduct 7n was obtained (Table 3, entry 9). Next,
diarylthiazolidin-2,4-diones with 4-MePh (5f) and 4-tBuPh (5g) on the 5-position were
subjected to conjugate addition reaction with 6a, affording adducts 7r−s with excellent
enantioselectivities and slightly lower but satisfactory diastereoselectivities (Table 3, entries
13−14). Unfortunately, 5-benzyl and ethyl-substituted as well as N-benzyl-substituted
thiazolidin-2,4-diones (5j-l) were unreactive under the established reaction conditions. The
absolute configurations of conjugate adducts 7 were assigned based on X-ray crystallographic
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analysis of a single crystal of 7f.10
Table 3. Substrate scope of conjugate addition to nitroolefinsa
7
8
9
O
O
catalyst G
(10 mol %)
m-xylene, -20 oC
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Ar
Ar
R
N
Ar'
N
+
NO2
Ar'
NO2
S
S
O
O
R
H
72-96 h
5: Ar = 4-MeOPh
6
7
1)
2)
O
O
3)
O
Ar
Ar
Ar
N
N
N
NO2
NO2
S
S
NO2
O
O
S
H
H
O
H
F
Cl
7f: 94% yield
97% (>99%) ee
17:1 (>19:1) dr
7g: 90% yield
95% ee
19:1 dr
7h: 88% yield
87% (>99%) ee
10:1 (19:1) dr
6)b
4)
5)
O
N
O
N
O
N
Ar
Ar
Ar
NO2
NO2
NO2
S
S
S
O
O
O
H
H
H
Cl
Br
Cl
7k: 84% yield
88% (>99%) ee
16:1 (19:1) dr
7i: 90% yield
90% ee, 11:1 dr
7j: 87% yield
99% ee, >19:1 dr
9)b
7)
8)
O
N
O
O
N
Ar
Ar
Ar
N
NO2
S
NO2
NO2
Me
O
H
S
S
O
O
H
H
Me
Me
7l: 89% yield
92% (94%) ee
14:1 (19:1) dr
7m: 97% yield
90% (93%) ee
11:1 (>19:1) dr
7n: 92% yield
96% ee
>19:1 dr
10)
11)
12)
O
N
O
N
O
N
Ar
Ar
Ar
O
NO2
NO2
S
S
O
NO2
O
H
S
H
H
S
MeO
7o: 92% yield
93% (>99%) ee
13:1 (>19:1) dr
7p: 91% yield
74% ee
>19:1 dr
7q: 63% yield
96% ee, 5:1 dr
13)
14)
Me
tBu
O
N
O
Ar
Ar
O
N
NO2
NO2
S
S
O
H
H
7r: 89% yield
90% ee, 10:1 dr
7s: 87% yield
87% ee, 8:1 dr
aThe reaction was carried out with 0.1 mmol of 5, 0.12 mmol of 6, 0.01 mmol of G, 0.01
mmol of NaCl and 50 mg of 4 Å molecular sieves in 1.0 mL m-xylene. Yields of isolated
1
products are presented. The dr was determined by H NMR analysis. Ee values were
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determined by HPLC using chiral stationary phase. The data in parentheses were obtained
6
7
after a single recrystallization. b15 mol% of catalyst G was utilized.
8
9
In recent years, asymmetric sulfenylation6a-b,11 has been demonstrated as one of the most
efficient strategies to build optically active sulfur-containing compounds. As an continuation
of the success in conjugate addition, we were subsequently engaged in surveying
sulfenylation of diarylthiazolidin-2,4-diones, to facilitate the first asymmetric synthesis of
5-sulfur-5-aryl-disubstituted thiazolidin-2,4-diones and 5-sulfone-5-aryl-disubstituted
thiazolidin-2,4-diones, which were tested as inhibitors for farnesyl-protein transferase.12
Under the established reaction conditions towards conjugate addition, we attempted
sulfenylation of diphenylthiazolidin-2,4-dione 5a using N-(benzylthio)succinimide 8a as the
sulfenylating reagent. However, the reaction became very sluggish, indicating that amino
acid-based urea−tertiary amine catalyst is not optimal for sulfenylation. We next screened
amino acid-based thiourea−tertiary amines, which is another class of important bifunctional
Brønsted base catalysts.13 We were pleased to find that the reaction worked, and the
sulfenylated adduct 9a was isolated in 85% yield with 87% ee after 12 hours when employing
L-tert-leucine-based thiourea−tertiary amine K as the catalyst and 5 Å molecular sieves as the
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o
additive in CHCl3 at −55 C (Table 4, entry 1). Moreover, 5e was found to yield higher
enantioselectivity (entry 4).9 The substituents on aromatic rings at 5-position of
thiazolidin-2,4-diones (5g-i) and of N-(benzylthio)succinimides (8b-d) did not affect the
reactivity and enantioselectivity (entries 5−10). However for N-(arylthio)succinimides, only
12% ee of 9k was obtained when using N-(phenylthio)succinimide 8e as the sufenylating
reagent. (entry 11).
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Table 4. Substrate scope of sulfenylationa
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7
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aThe reaction was carried out with 0.1 mmol of 5, 0.2 mmol of 8, 0.01 mmol of K, and 10
mg of 5Å molecular sieves in 0.5 mL CHCl3. Yields of isolated products are presented. Ee
values were determined by HPLC using chiral stationary phase.
OPh
OMe
H
O
H
H
S
N
H
O
N
H
N
H
N
H
N
N
O
H
Ar
Ar
O
O
O
N
N
N
N
RS
O
O
Ar'
Ar'
S
S
O
R
TS-1
TS-2
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Figure 3. Plausible transition states of two reactions.
6
On the basis of our previous investigations,7 the plausible transition states of two reactions
were proposed (Figure 3). First, the enolates of diarylthiazolidin-2,4-diones were generated
after protonation and would bind to the R3NH+ arm of the catalysts G or K. Two N−H bonds
of (thio)urea unit could activate the LUMO of nitroolefins (TS-1) or
N-(sulfanyl)-succinimides (TS-2) through two H-bonding interactions. The conjugate adducts
7 and sulfenylated adducts 9 were thus obtainable with the observed absolute configurations
after nucleophilic addition. The used additives, such as 4 Å and 5 Å molecular sieves as well
as NaCl, should affect the solution environment to increase the free energy differences
between the transition states, thus leading to slightly improved enantio- and
diastereoselectivity in two transformations.
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Table 5. IC50 values of chiral conjugate adducts 7 on the growth of human cancer cell
linesa
compound
H22
7f
21
36
29
7g
55
7h
20
7j
25
7l
18
7m
40
7n
9.9
30
45
HCT116
K562
94
45
73
60
94
>100
>100
>100
>100
>100
aValues are means of three experiments each done in duplicate. IC50 values are described in
μM.
To demonstrate the utility of the methodology, we endeavored to evaluate the biological
activities of adducts. A variety of chiral 5-aryl-5-substituted thiazolidin-2,4-diones, including
7f-h, 7j and 7l, were subjected to cytotoxic activity measurements for three human cancer cell
lines employing the MTT assay. A summary of the IC50 values is shown in Table 5. The
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analogues 7f, 7h, 7j and 7l showed inhibitory effects on the H22 with IC50 values of 18 to 25
μM. Moreover, 7n gave a lower IC50 value of 9.9 μM. While 7n and 7f presented weaker
inhibitory activity (IC50 = 30 μM, 29 μM) on the HCT116 and K562 respectively, they were
still overall the most effective compounds. The distinct cytotoxicities suggested that the
cancer cell lines exhibited different sensitivities to chiral 5-aryl-5-substituted
thiazolidinediones.
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We also attempted transformation of adducts 9 to verify the synthetic utility of the method.
Using mCPBA in dichloromethane, the oxidation of the sulfenylated adduct 9d was
performed as shown in Scheme 2. After 2 hours when the reaction completed, the sulfone 10
could be readily achieved in 81% yield with no loss of enantiomeric purity. The absolute
configurations of sulfenylated adducts 9 could be assigned based on X-ray crystallographic
analysis of a single crystal of sulfone 10.10
Scheme 2. Transformation of adducts 9.
CONCLUSION
In summary, we have established the pioneer work of employing
diarylthiazolidin-2,4-diones as nucleophiles in asymmetric synthesis. By utilizing an L-amino
acid-based tertiary amine as a bifunctional Brønsted base catalyst, asymmetric conjugate
addition of diarylthiazolidin-2,4-diones to nitroolefins afforded a series of chiral
5-aryl-5-substituted thiazolidin-2,4-diones, which structurally feature two contiguous
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thia-quaternary and tertiary stereogenic centers, with high enantio- and diastereoselectivities
(up to >99% ee and >19:1 dr). Several conjugate adducts have been observed to show
potential anticancer activities. Moreover, a highly enantioselective sulfenylation of
diarylthiazolidin-2,4-diones to N-(sulfanyl)-succinimides has been developed, leading to
chiral 5-sulfur-5-aryl-disubstituted thiazolidin-2,4-diones and 5-sulfone-5-aryl-disubstituted
thiazolidin-2,4-diones. Given our devised expedient synthetic approach to various
5H-thiazolidin-2,4-diones with highly tunable N-substituents, we anticipate that such novel
nucleophilic reagents will find application in more kinds of reaction requiring access to
diverse chiral 5,5-disubstituted thiazolidinediones with potentially positive biological and
pharmaceutical activities.
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EXPERIMENTAL SECTION
General information
General Procedures and Methods
Experiments involving moisture and/or air sensitive components were performed under a
positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet.
Dried solvents and liquid reagents were transferred by oven-dried syringes or hypodermic
syringe cooled to ambient temperature in a desiccator. Reactions mixtures were stirred in 10
mL sample vial with Teflon-coated magnetic stirring bars unless otherwise stated. Moisture in
non-volatile reagents/compounds was removed in high vacuo by means of an oil pump and
subsequent purging with nitrogen. Solvents were removed in vacuo under ~30 mmHg and
o
heated with a water bath at 30−35 C using rotary evaporator with aspirator. The condenser
was cooled with running water at 0 oC.
All experiments were monitored by analytical thin layer chromatography (TLC). TLC was
performed on pre-coated plates. After elution, plate was visualized under UV illumination at
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254 nm for UV active material. Further visualization was achieved by staining KMnO4, ceric
molybdate, or anisaldehyde solution. For those using the aqueous stains, the TLC plates were
heated on a hot plate.
9
Columns for flash chromatography (FC) contained silica gel 200-300 mesh. Columns were
packed as slurry of silica gel in petroleum ether and equilibrated solution using the
appropriate solvent system. The elution was assisted by applying pressure of about 2 atm with
an air pump.
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Instrumentations
Proton nuclear magnetic resonance (1H NMR) and carbon NMR (13C NMR) were recorded in
1
CDCl3 otherwise stated. H (300 MHz) and 13C (75 MHz) were performed on (300 MHz)
spectrometers. Chemical shifts are reported in parts per million (ppm), using the residual
solvent signal as an internal standard: CDCl3 (1H NMR: δ 7.26, singlet; 13C NMR: δ 77.0,
triplet). Multiplicities were given as: s (singlet), d (doublet), t (triplet), q (quartet), quintet, m
(multiplets), dd (doublet of doublets), dt (doublet of triplets), and br (broad). Coupling
constants (J) were recorded in Hertz (Hz). The number of proton atoms (n) for a given
resonance was indicated by nH. The number of carbon atoms (n) for a given resonance was
indicated by nC. HRMS (analyzer: TOF) was reported in units of mass of charge ratio (m/z).
Optical rotations were recorded on a polarimeter with a sodium lamp of wavelength 589 nm
and reported as follows; []TC (c = g/100 mL, solvent). Melting points were determined on
a microscopic melting point apparatus.
Enantiomeric excesses were determined by chiral High Performance Liquid Chromatography
(HPLC) analysis. UV detection was monitored at 254 nm. HPLC samples were dissolved in
HPLC grade isopropanol (IPA) unless otherwise stated.
Materials
All commercial reagents were purchased with the highest purity grade. They were used
without further purification unless specified. All solvents used, mainly petroleum ether (PE)
and ethyl acetate (EtOAc) were distilled. Anhydrous DCM and MeCN were freshly distilled
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from CaH2 and stored under N2 atmosphere. THF, Et2O, m-xylene and toluene were freshly
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distilled from sodium/benzophenone before use. Anhydrous methanol and etanol were
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8
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distilled from Mg. All compounds synthesized were stored in a −20 C freezer and
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light-sensitive compounds were protected with aluminium foil.
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General procedure for the synthesis of 2
A flame-dried 50 mL two-necked round bottomed flask equipped with a reflux condenser, a
teflon-coated magnetic stirring bar, a rubber septum, and an inlet adapter with three-way
stopcock was charged with 1 (2.77 mmol), NBS (540 mg, 3.05 mmol), and CCl4 (5.5 mL). To
the solution was added AIBN (23 mg, 0.14 mmol). The mixture was heated at reflux for 2
hours, then diluted with hexanes and filtered through a pad of celite. The filtrate was
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (hexanes-Et2O = 2:1) to afford 2 as a white solid.
General procedure for the synthesis of 4.
A mixture of 2 (white solid, 2.0 mmol), thiourea (2.0 mmol), sodium acetate (2.0 mmol) and
ethanol (10 mL) was stirred under reflux for 5 hours, and concentrated in vacuo. The residue
was neutralized with saturated aqueous sodium bicarbonate, and Et2O (10 mL) with hexane
(50 mL) were then added. The mixture was stirred at room temperature for 15 minutes, and
the imino compounds were collected by filtration.
General procedure for the synthesis of 5
A mixture of 4 (0.1 mmol), 4 N HCl (1.0 mL) and ethanol (5.0 mL) was stirred under reflux
for 13 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with
water, neutralized with saturated aqueous sodium bicarbonate and extracted with chloroform.
The organic layer was then washed with brine, dried with anhydrous magnesium sulphate and
concentrated in vacuo to give the title compounds.
General procedure for the synthesis of 7.
5-Argio-3-(4-methoxyphenyl)thiazolidine-2,4-dione 5 (0.1 mmol, 1.0 equiv), nitroolefin 6
(0.12 mmol, 1.2 equiv), G (0.01 mmol, 0.1 equiv), NaCl (0.1 equiv) and 4 Å molecular sieves
(50 mg) were dissolved in m-xylene (1.0 mL). The reaction mixture was stirred at −20 oC for
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72−96 hours and monitored by TLC. Upon complete consumption of 5, the reaction mixture
was concentrated under reduced pressure. The crude material was subsequently purified by
flash column chromatography on silica gel with PE/EtOAc mixture (20:1–5:1 ratio, the crude
material was completely dissolved in CH2Cl2/PE before loaded on silica gel). After removing
the solvent in vacuo, the product 7 could be obtained.
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Procedure for the synthesis of 9
5-Argio-3-(4-methoxyphenyl)thiazolidine-2,4-dione 5 (0.1 mmol, 1.0 equiv), 8 (0.2 mmol, 2
equiv), K (0.01 mmol, 0.1 equiv), and 5 Å molecular sieves (10 mg) were dissolved in CHCl3
(0.5 mL). The reaction mixture was stirred at −55 oC for 12−24 hours and monitored by TLC.
Upon complete consumption of 9, the reaction mixture was concentrated under reduced
pressure, the recovered crude material was subsequently purified by flash column
chromatography on silica gel with PE/EtOAc mixture (20:1–5:1 ratio, the crude material was
completely dissolved in CH2Cl2/PE before loaded on silica gel). After removing the solvent in
vacuo, the product 9 could be obtained.
General procedure for the synthesis of 10
o
A solution of 9d (210 mg, 0.5 mmol) in dichloromethane (5 mL) was cooled to 0 C and
mCPBA (215 mg, 1.25 mmol) was added. After stirring for 10 min, the solution was warmed
to room temperature, ant then stirred for two hours. The solvent was removed under vacuum,
and the residue was purified by column chromatography on silica gel to give 11 as a white
solid.
Gerneral methods for procedure of the biological studies
H22, HCT116 and K562 cells were seeded at a density of 4000−5000 cells in 96-well plates.
Compounds were added 24 hours after seeding. After 2 days in culture, the MTT stock
o
solution (5 mg/mL in PBS) was added to each well and incubated at 37 C for 4 hours. The
medium was removed carefully, and dimethyl sulfoxide was added to each well to dissolve
formazan. The absorbance of each well at 490 nm was measured by using a BioTek
microplate reader.
o
3,5-Diphenylthiazolidine-2,4-dione (5a),9d White solid; Mp 169.2–171.0 C; 216.3 mg (1
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mmol), 80% yield; 1H NMR (300 MHz, CDCl3) δ 7.60–7.39 (m, 8H), 7.31 (dd, J = 10.0, 3.1,
2H), 5.47 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 172.2, 170.4, 134.2, 132.8, 129.5, 129.4 (two
peaks), 129.3, 128.3, 127.3, 53.0; HRMS (ESI) m/z 270.0588 (M+H+), Calcd for C15H12NO2S
270.0589.
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5-Phenyl-3-(p-tolyl)thiazolidine-2,4-dione (5b), White solid; Mp 187.0–188.2 oC; 235.6 mg
(1 mmol), 83% yield; 1H NMR (300 MHz, CDCl3) δ 7.57–7.38 (m, 5H), 7.28 (t, J = 11.7, 2H),
7.16 (d, J = 7.8, 2H), 5.43 (s, 1H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.3, 170.5,
139.5, 134.3, 130.2, 130.1, 129.3, 129.2, 128.3, 127.0, 53.0, 21.3; HRMS (ESI) m/z 284.0746
(M+H+), Calcd for C16H14NO2S 284.0745.
o
3-(4-Chlorophenyl)-5-phenylthiazolidine-2,4-dione (5c), White solid; Mp 133.5–134.7 C;
251.5 mg (1 mmol), 83% yield; 1H NMR (300 MHz, CDCl3) δ 7.50–7.31 (m, 6H), 7.16 (d, J
= 8.9, 3H), 5.37 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 171.9, 170.0, 135.3, 133.8, 131.2,
129.7, 129.4, 129.4, 128.6, 128.2, 53.1; HRMS (ESI) m/z 304.0201 (M+H+), Calcd for
C15H11ClNO2S 304.0199.
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3-(3-Chlorophenyl)-5-phenylthiazolidine-2,4-dione (5d), White solid; Mp 125.0–126.3 C;
1
227.3 mg (1 mmol), 75% yield; H NMR (300 MHz, CDCl3) δ 7.55–7.39 (m, 7H), 7.32 (s,
1H), 7.24–7.16 (m, 1H), 5.41 (s, 1H); 13C NMR (75 MHz, DMSO) δ 173.0, 170.8, 135.7,
134.3, 132.6, 130.4, 130.1, 129.7, 129.5, 129.4, 129.3, 125.7, 53.1; HRMS (ESI) m/z
304.0197 (M+H+), Calcd for C15H11ClNO2S 304.0199.
5-Phenyl-3-(m-tolyl)thiazolidine-2,4-dione (5e), White solid; Mp 154.3–155.3 oC; 224.4 mg
(1 mmol), 79% yield; 1H NMR (300 MHz, DMSO) δ 6.58 (d, J = 6.9, 2H), 6.43 (t, J = 8.1,
4H), 6.31 (d, J = 7.4, 1H), 6.22 (d, J = 12.2, 2H), 4.96 (s, 1H), 1.36 (s, 3H); 13C NMR (75
MHz, DMSO) δ 173.2, 171.0, 139.4, 135.8, 133.8, 130.3, 129.6, 129.5, 129.3, 128.8, 125.6,
53.0, 21.2; HRMS (ESI) m/z 284.0743 (M+H+), Calcd for C16H14NO2S 284.0745.
3-(4-Methoxyphenyl)-5-phenylthiazolidine-2,4-dione (5f), White solid; Mp 169.7–171.0 oC;
243.2 mg (1 mmol), 81% yield; 1H NMR (300 MHz, CDCl3) δ 7.60–7.35 (m, 5H), 7.23–7.12
(m, 2H), 6.99 (d, J = 9.0, 2H), 5.42 (s, 1H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.4,
170.6, 160.0, 134.3, 129.4, 129.3, 128.5, 128.3, 125.4, 114.8, 55.6, 53.0; HRMS (ESI) m/z
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300.0695 (M+H+), Calcd for C16H14NO3S 300.0694.
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3-(4-Methoxyphenyl)-5-(p-tolyl)thiazolidine-2,4-dione (5g), White solid; Mp 162.3–163.5
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8
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oC; 266.1 mg (1 mmol), 85% yield; H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 8.1, 2H),
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7.37–7.15 (m, 4H), 7.14–6.85 (m, 2H), 5.47 (s, 1H), 3.91 (s, 3H), 2.46 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 172.6, 170.7, 160.0, 139.3, 131.2, 130.0, 128.5, 128.1, 125.4, 114.7, 55.6,
52.8, 21.2; HRMS (ESI) m/z 314.0852 (M+H+), Calcd for C17H16NO3S 314.0851.
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5-(4-(tert-Butyl)phenyl)-3-(4-methoxyphenyl)thiazolidine-2,4-dione (5h), White solid; Mp
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182.9–184.1 C; 287.6 mg (1 mmol), 81% yield; H NMR (300 MHz, CDCl3) δ 7.43 (q, J =
8.6, 4H), 7.25–7.12 (m, 2H), 7.05–6.87 (m, 2H), 5.41 (s, 1H), 3.83 (s, 3H), 1.33 (s, 9H);13C
NMR (75 MHz, CDCl3) δ 172.7, 170.8, 160.0, 152.4, 131.2, 128.6, 127.9, 126.4, 125.4, 114.7,
55.6, 52.7, 34.7, 31.3; HRMS (ESI) m/z 356.1321 (M+H+), Calcd for C20H22NO3S 356.1320.
5-(4-Chlorophenyl)-3-(4-methoxyphenyl)thiazolidine-2,4-dione (5i), White solid; Mp
169.2–170.4 oC; 259.8 mg (1 mmol), 78% yield; 1H NMR (300 MHz, CDCl3) δ 7.42 (s, 4H),
7.17 (d, J = 8.5, 2H), 6.99 (d, J = 8.4, 2H), 5.40 (s, 1H), 3.83 (s, 3H); 13C NMR (75 MHz,
D6-acetone) δ 172.3, 170.1, 160.0, 134.6, 134.2, 130.6, 129.1, 126.2, 114.3, 55.0, 51.9;
HRMS (ESI) m/z 334.0306 (M+H+), Calcd for C16H13ClNO3S 334.0305.
5-(3-Fluorophenyl)-3-(4-methoxyphenyl)thiazolidine-2,4-dione (5j), White solid; Mp
139.7–141.3 oC; 256.8 mg (1 mmol), 81% yield; 1H NMR (300 MHz, CDCl3) δ 7.44 (dd, J =
13.8, 7.9, 2H), 7.25 – 7.10 (m, 4H), 7.02 (d, J = 8.9, 2H), 5.44 (s, 1H), 3.86 (s, 3H);13C NMR
(75 MHz, CDCl3) δ 171.8, 170.1, 164.7, 161.4, 160.1, 136.4, 136.3, 131.0, 130.9, 128.4,
125.2, 124.1, 124.1, 116.5, 116.3, 115.6, 115.3, 114.8, 55.6, 52.4; HRMS (ESI) m/z 318.0601
(M+H+), Calcd for C16H13FNO3S 318.0600.
5-Benzyl-3-(4-methoxyphenyl)thiazolidine-2,4-dione (5k), White solid; Mp 138.2–139.6 oC;
1
247.3 mg (1 mmol), 79% yield; H NMR (300 MHz, CDCl3) δ 7.47–7.20 (m, 5H), 6.96 (s,
4H), 4.60 (dd, J = 8.2, 3.4, 1H), 3.80 (s, 3H), 3.53–3.26 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 173.5, 170.6, 160.0, 135.3, 129.6, 128.7, 128.5, 127.7, 125.2, 114.7, 55.5, 51.0, 38.6;
HRMS (ESI) m/z 314.0852 (M+H+), Calcd for C17H16NO3S 314.0851.
o
5-Ethyl-3-(4-methoxyphenyl)thiazolidine-2,4-dione (5l),9a White solid; Mp 87.8–88.4 C;
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195.8 mg (1 mmol), 78% yield; 1H NMR (300 MHz, CDCl3) δ 7.15 (d, J = 8.6, 2H), 6.99 (d, J
= 8.6, 2H), 4.33 (dd, J = 8.0, 4.1, 1H), 3.82 (s, 3H), 2.38–1.95 (m, 2H), 1.12 (t, J = 7.3, 3H);
13C NMR (75 MHz, CDCl3) δ 174.2, 171.1, 159.9, 128.5, 125.3, 114.7, 55.5, 50.9, 26.4, 10.7;
HRMS (ESI) m/z 252.0695 (M+H+), Calcd for C12H14NO3S 252.0694.
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3-Benzyl-5-phenylthiazolidine-2,4-dione (5m), White solid; Mp 148.8–150.3 C; 189.6 mg
(1 mmol), 67% yield; 1H NMR (300 MHz, DMSO) δ 7.73–7.03 (m, 10H), 5.96 (s, 1H), 4.76
(s, 2H); 13C NMR (75 MHz, DMSO) δ 173.6, 171.4, 136.0, 135.6, 129.5, 129.2, 129.1, 129.1,
128.3, 128.0, 52.8, 45.3; HRMS (ESI) m/z 284.0746 (M+H+), Calcd for C16H14NO2S
284.0745.
(S)-5-((S)-2-Nitro-1-phenylethyl)-3,5-diphenylthiazolidine-2,4-dione (7a), White solid; Mp
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139.4–140.2 C; 89% ee; dr = 9:1; 36.4 mg (0.1 mmol), 87% yield; [α]D +27.3 (c 1.00,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 7.5, 2H), 7.70–7.28 (m, 11H), 6.51 (d, J =
7.2, 2H), 5.08 – 4.74 (m, 2H), 4.44–4.40 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.7, 167.4,
134.3, 132.4, 132.2, 131.6, 130.1, 129.9, 129.6, 129.4, 129.3, 128.9, 128.0, 127.1, 75.7, 69.0,
53.0; HRMS (ESI) m/z 419.1064 (M+H+), Calcd for C23H19N2O4S 419.1066. The ee was
determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm) + CHIRALPAK IA
o
(4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 C; 254 nm;
tR = 25.8 min (minor, major diastereomer), 28.7 min (minor diastereomer), 33.5 min (major,
major diastereomer), 40.2 min (minor diastereomer).
(S)-5-((S)-2-Nitro-1-phenylethyl)-5-phenyl-3-(p-tolyl)thiazolidine-2,4-dione. (7b), White
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solid; Mp 153.3–154.5 C; 86% ee; dr = 7:1; 35.1 mg (0.1 mmol), 81% yield; [α]D +24.6 (c
1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 7.4, 2H), 7.66–7.34 (m, 8H), 7.11 (d,
J = 7.6, 2H), 6.38 (d, J = 7.5, 2H), 4.99 – 4.73 (m, 2H), 4.43–4.40 (m, 1H), 2.31 (s, 3H);13C
NMR (75 MHz, CDCl3) δ172.8, 167.5, 139.7, 134.3, 132.4, 130.1, 129.9, 129.8, 129.6, 129.5,
128.8, 128.0, 126.8, 75.7, 69.0, 53.0, 21.2; HRMS (ESI) m/z 433.1223 (M+H+), Calcd for
C24H21N2O4S 433.1222. The ee was determined by HPLC analysis. CHIRALPAK IA (4.6 mm
o
i.d. x 250 mm); Hexane/2-propanol = 95/5; flow rate 1.0 mL/min; 25 C; 254 nm; tR = 21.2
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min (minor diastereomer), 32.9 min (minor, major diastereomer), 37.7 min (major, major
diastereomer), 42.3 min (minor diastereomer).
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(S)-3-(4-Chlorophenyl)-5-((S)-2-nitro-1-phenylethyl)-5-phenylthiazolidine-2,4-dione. (7c),
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White solid; Mp 144.6–146.0 C; 82% ee; dr = 6:1; 42.2 mg (0.1 mmol), 94% yield; [α]D
+21.2 (c 1.00, CHCl3); 1H NMR (300 MHz, DMSO) δ 8.01 (d, J = 7.2, 2H), 7.56–7.44 (m,
10H), 6.57 (d, J = 8.2, 2H), 5.31–5.21 (m, 1H), 4.84 (d, J = 11.1, 1H), 4.66 (d, J = 13.2, 1H);
13C NMR (75 MHz, CDCl3) δ 172.5, 167.1, 135.5, 134.0, 132.4, 130.5, 130.0, 130.0 129.9,
129.6, 129.5, 128.9, 128.4, 128.0, 75.6, 69.1, 53.0; HRMS (ESI) m/z 453.0673 (M+H+),
Calcd for C23H18ClN2O4S 453.0676. The ee was determined by HPLC analysis. CHIRALPAK
o
IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 C; 254
nm; tR = 12.9 min (minor, major diastereomer), 17.4 min (minor diastereomer), 29.4 min
(major, major diastereomer), 32.7 min (minor diastereomer).
(S)-5-((S)-2-Nitro-1-phenylethyl)-5-phenyl-3-(m-tolyl)thiazolidine-2,4-dione.(7e), White
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solid; Mp 227.8–228.2 C; 87% ee; dr = 9:1; 30.8 mg (0.1 mmol), 71% yield; [α]D +30.5 (c
1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 7.3, 2H), 7.54–7.26 (m, 8H),
7.23–7.01 (m, 2H), 6.50–6.04 (m, 2H), 5.05–4.69 (m, 2H), 4.48–4.40 (m, 1H), 2.26 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 172.8, 167.4, 139.5, 134.3, 132.5, 132.0, 130.3, 130.1, 129.9,
129.6, 129.5, 129.0, 128.9, 128.0, 127.7, 124.1, 75.7, 69.1, 53.0, 21.1; HRMS (ESI) m/z
433.1223 (M+H+), Calcd for C24H21N2O4S 433.1222. . The ee was determined by HPLC
analysis. Nu-Analytical INA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 95/5; flow rate
o
1.0 mL/min; 25 C; 254 nm; tR = 24.7 min (minor, major diastereomer), 29.3 min (minor
diastereomer), 31.3 min (minor diastereomer), 34.4 min (major, major diastereomer).
(S)-3-(4-Methoxyphenyl)-5-((S)-2-nitro-1-phenylethyl)-5-phenylthiazolidine-2,4-dione (7f),
White solid; Mp 144.6–146.0 oC; 97% ee; dr = 16:1 (after a single recrystallization, ee > 99%,
dr >19:1); 42.2 mg (0.1 mmol), 94% yield; [α]2D2 +21.2 (c 1.00, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 8.06 (d, J = 7.0,2H), 7.54–7.41 (m, 8H), 6.81 (d, J = 8.9, 2H), 6.41 (d, J = 8.9, 2H),
13
5.02–4.75 (m, 2H), 4.43–4.40 (m, 1H), 3.76 (s, 3H); C NMR (75 MHz, CDCl3) δ 172.9,
167.7, 160.1, 134.3, 132.5, 130.1, 130.0, 129.6, 129.5, 128.9, 128.3, 128.1, 124.6, 114.6, 75.7,
68.9, 55.5, 53.0; HRMS (ESI) m/z 449.1176 (M+H+), Calcd for C24H21N2O5S 449.1171. The
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ee was determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm) +
CHIRALPAK IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min;
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25 C; 254 nm; tR = 29.6 min (minor, major diastereomer), 37.6 min (minor diastereomer),
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51.7 min (major, major diastereomer), 56.8 min (minor diastereomer).
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(S)-5-((S)-1-(4-Fluorophenyl)-2-nitroethyl)-3-(4-methoxyphenyl)-5-phenylthiazolidine-2,
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4-dione (7g), White solid; Mp 97.3–98.9 C; 95% ee; dr > 19:1; 41.9 mg (0.1 mmol), 90%
yield; [α]2D2 +20.6 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.03 (dd, J = 8.1, 1.3, 2H),
7.68–7.41 (m, 5H), 7.11 (t, J = 8.6, 2H), 6.94–6.76 (m, 2H), 6.49 (d, J = 8.9, 2H), 4.95–4.68
(m, 2H), 4.41 (dd, J = 12.8, 3.5, 1H), 3.77 (s, 3H);13C NMR (75 MHz, CDCl3) δ 172.9, 167.4,
163.2 (d, 1JC-F = 248.3 Hz), 160.2, 134.2, 131.9 (d, 1JC-F = 8.2 Hz), 129.9, 129.6, 128.1,
127.9, 124.5, 116.0, 115.8, 114.7, 75.7, 68.8, 55.5, 52.2;HRMS (ESI) m/z 467.1072 (M+H+),
Calcd for C24H20FN2O5S 467.1077. The ee was determined by HPLC analysis. Nu-Analytical
o
INA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 95/5; flow rate 1.0 mL/min; 25 C; 254
nm; tR = 41.6 min (minor diastereomer), 43.3 min (minor, major diastereomer), 48.8 min
(major, major diastereomer), 70.0 min (minor diastereomer).
(S)-5-((S)-1-(4-Chlorophenyl)-2-nitroethyl)-3-(4-methoxyphenyl)-5-phenylthiazolidine-2,
o
4-dione (7h), White solid; Mp 163.1–164.6 C; 87% ee; dr = 11:1 (after a single
recrystallization, ee > 99%, dr >19:1); 42.4 mg (0.1 mmol), 88% yield; [α]2D2 +19.9 (c 1.00,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.05 (dd, J = 8.1, 1.4, 2H), 7.64–7.19 (m, 7H),
6.96–6.76 (m, 2H), 6.56–6.43 (m, 2H), 5.00–4.73 (m, 2H), 4.44 (dd, J = 12.6, 3.2, 1H), 3.80
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.8, 167.3, 160.2, 135.7, 134.1, 131.4, 130.9, 129.9,
129.6, 129.1, 128.0, 124.5, 114.7, 75.5, 68.7, 55.5, 52.4; HRMS (ESI) m/z 483.0778 (M+H+),
Calcd for C24H20ClN2O5S 483.0781. The ee was determined by HPLC analysis. CHIRALPAK
IA (4.6 mm i.d. x 250 mm) + CHIRALPAK IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol
= 80/20; flow rate 1.0 mL/min; 25 oC; 254 nm; tR = 30.1 min (minor diastereomer), 39.4 min
(minor, major diastereomer), 53.4 min (major, major diastereomer), 65.8 min (minor
diastereomer).
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(S)-5-((S)-1-(3-Chlorophenyl)-2-nitroethyl)-3,5-diphenylthiazolidine-2,4-dione (7i), White
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solid; Mp 74.1–75.7 C; 90% ee; dr = 19:1; 43.4 mg (0.1 mmol), 90% yield; [α]D +21.2 (c
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1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 8.27 (dd, J = 8.1, 1.5, 2H), 7.97–7.42 (m, 7H),
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7.21–7.02 (m, 2H), 6.90–6.67 (m, 2H), 5.37–4.88 (m, 2H), 4.66 (dd, J = 12.8, 3.2, 1H), 4.03
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.8, 167.2, 160.2, 134.9, 134.0, 133.4, 132.7, 130.3,
130.0, 129.6, 128.3, 128.2, 128.0, 124.5, 122.8, 114.7, 75.3, 68.5, 55.5, 52.4; HRMS (ESI)
m/z 483.0781 (M+H+), Calcd for C24H20ClN2O5S 483.0782. The ee was determined by HPLC
analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm) + CHIRALPAK IE (4.6 mm i.d. x 250
mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 oC; 254 nm; tR = 24.6 min (minor,
major diastereomer), 31.4 min (minor diastereomer), 35.9 min (minor diastereomer), 41.4 min
(major, major diastereomer).
(S)-5-((S)-1-(3-Bromophenyl)-2-nitroethyl)-3-(4-methoxyphenyl)-5-phenylthiazolidine-2,
4-dione (7j), White solid; Mp 116.7–118.1 oC; 99% ee; dr > 19:1; 45.8 mg (0.1 mmol), 87%
yield; [α]2D2 +20.8 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.27 (dd, J = 8.1, 1.5, 2H),
8.00–7.63 (m, 6H), 7.54 (dd, J = 13.1, 5.2, 1H), 7.22–6.96 (m, 2H), 6.93–6.51 (m, 2H),
5.17–4.95 (m, 2H), 4.66 (dd, J = 12.8, 3.2, 1H), 4.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
172.8, 167.2, 160.2, 134.9, 134.0, 133.4, 132.7, 130.3, 130.0, 129.6, 128.3, 128.2, 128.0,
124.5, 122.8, 114.7, 75.3, 68.5, 55.5, 52.4; HRMS (ESI) m/z 527.0285 (M+H+), Calcd for
C24H20BrN2O5S 527.0276. The ee was determined by HPLC analysis. CHIRALPAK IA (4.6
mm i.d. x 250 mm) + CHIRALPAK IE (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 95/5;
o
flow rate 0.5 mL/min; 25 C; 254 nm tR = 30.4 min (minor diastereomer), 32.8 min (major,
major diastereomer), 55.6 min (minor, major diastereomer), 62.6 min (minor diastereomer).
(S)-5-((S)-1-(2-Chlorophenyl)-2-nitroethyl)-3-(4-methoxyphenyl)-5-phenylthiazolidine-2,
o
4-dione (7k), White solid; Mp 156.3–157.1 C; 88% ee; dr = 16:1 (after a single
recrystallization, ee > 99%, dr >19:1); 40.5 mg (0.1 mmol), 84% yield, [α]2D2 +23.2 (c 1.00,
CHCl3);1H NMR (300 MHz, CDCl3) δ 8.17–7.98 (m, 2H), 7.67–7.30 (m, 7H), 6.81 (d, J = 8.9,
2H), 6.46 (d, J = 8.9, 2H), 5.66 (dd, J = 11.1, 4.0, 1H), 4.93–4.68 (m, 1H), 4.58 (dd, J = 13.2,
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4.1, 1H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.2, 167.5, 160.2, 137.0, 134.7, 131.7,
130.9, 130.5, 129.9, 129.4, 128.2, 127.2, 124.8, 114.6, 134.9, 68.4, 55.5, 52.9, 47.5; HRMS
(ESI) m/z 483.0781 (M+H+), Calcd for C24H20ClN2O5S 483.0780. The ee was determined by
HPLC analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm) + CHIRALPAK IA (4.6 mm i.d. x
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o
250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 C; 254 nm; tR = 13.7 min
(minor, major diastereomer), 14.7 min (major, major diastereomer), 22.8 min (minor
diastereomer), 36.1 min (minor diastereomer).
(S)-3-(4-methoxyphenyl)-5-((S)-2-nitro-1-(p-tolyl)ethyl)-5-phenylthiazolidine-2,4-dione
(7l), White solid; Mp 159.5–161.1 oC; 92% ee; dr = 14:1 (after a single recrystallization, ee =
94%, dr = 19:1); 41.1 mg (0.1 mmol), 89% yield; [α]2D2 +24.0 (c 1.00, CHCl3); 1H NMR (300
MHz, CDCl3) δ 8.09–7.85 (m, 2H), 7.59–7.26 (m, 5H), 7.28–7.09 (m, 2H), 6.78 (d, J = 9.0,
2H), 6.41 (t, J = 6.0, 2H), 4.95–4.66 (m, 2H), 4.37–4.34 (m, 1H), 3.75 (s, 3H), 2.33 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 173.0, 167.8, 160.1, 139.5, 134.4, 129.9, 129.8, 129.5, 129.3,
128.3, 128.1, 124.7, 114.5, 75.8, 69.1, 55.5, 52.8, 21.2; HRMS (ESI) m/z 463.1321 (M+H+),
Calcd for C25H23N2O5S 463.1328. The ee was determined by HPLC analysis. CHIRALPAK
IA (4.6 mm i.d. x 250 mm) + CHIRALPAK IE (4.6 mm i.d. x 250 mm); Hexane/2-propanol =
o
80/20; flow rate 1.0 mL/min; 25 C; 254 nm; tR =46.6 min (minor, major diastereomer), 50.4
min (minor diastereomer), 69.0 min (major, major diastereomer), 82.3 min (minor
diastereomer).
(S)-3-(4-Methoxyphenyl)-5-((S)-2-nitro-1-(m-tolyl)ethyl)-5-phenylthiazolidine-2,4-dione
(7m), White solid; Mp 143.6–145.2 oC; 90% ee; dr = 11:1 (after a single recrystallization, ee
= 93%, dr >19:1); 44.8 mg (0.1 mmol), 97% yield; [α]2D2 +25.0 (c 1.00, CHCl3); 1H NMR (300
MHz, CDCl3) δ 8.01 (d, J = 7.0, 2H), 7.59–7.38 (m, 3H), 7.40–7.11 (m, 4H), 6.78 (d, J = 8.9,
2H), 6.39 (d, J = 8.9, 2H), 4.98–4.69 (m, 2H), 4.41–4.34 (m, 1H), 3.72 (s, 3H), 2.33 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 172.9, 167.8, 160.1, 138.6, 134.4, 132.4, 130.9, 130.2, 129.8,
129.5, 128.7, 128.3, 128.2, 126.8, 124.7, 114.5, 75.7, 69.0, 55.5, 53.0, 21.5; HRMS (ESI) m/z
463.1318 (M+H+), Calcd for C25H23N2O5S 463.1328. The ee was determined by HPLC
analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm) + CHIRALPAK IA (4.6 mm i.d. x 250
mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 oC; 254 nm; tR = 22.9 min (minor,
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major diastereomer), 33.2 min (minor diastereomer), 38.9 min (major, major diastereomer),
44.5 min (minor diastereomer).
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(7n), White solid; Mp 142.9–144.0 C; 99% ee; dr > 19:1; 42.5 mg (0.1 mmol), 92% yield;
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[α]2D2 +20.4 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.13–7.86 (m, 3H), 7.61–7.46 (m,
3H), 7.36–7.27 (m, 3H), 6.89–6.67 (m, 2H), 6.65–6.09 (m, 2H), 5.24 (dd, J = 11.3, 3.8, 1H),
4.87 (dd, J = 13.0, 11.3, 1H), 4.48 (dd, J = 13.1, 3.8, 1H), 3.74 (s, 3H), 2.59 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 173.0, 167.8, 160.1, 139.6, 135.1, 131.8, 129.8, 129.5, 129.4, 129.2,
128.5, 128.3, 128.2, 129.5, 114.6, 68.9, 55.5, 52.9, 47.2, 20.1; HRMS (ESI) m/z 485.1148
(M+Na+), Calcd for C25H23N2O5S 485.1147. The ee was determined by HPLC analysis.
CHIRALPAK IA (4.6 mm i.d. x 250 mm) + CHIRALPAK IE (4.6 mm i.d. x 250 mm);
o
Hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 C; 254 nm; tR = 27.1 min (major,
major diastereomer), 31.6 min (minor, major diastereomer), 55.6 min (minor diastereomer),
58.5 min (minor diastereomer).
(S)-3-(4-Methoxyphenyl)-5-((S)-1-(4-methoxyphenyl)-2-nitroethyl)-5-phenylthiazolidine-
o
2,4-dione (7o), White solid; Mp 81.0–82.3 C; 93% ee; dr = 12:1 (after a single
recrystallization, ee > 99%, dr >19:1); 44.0 mg (0.1 mmol), 92% yield; [α]2D2 +21.7 (c 1.00,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.04 (dd, J = 8.1, 1.2, 2H), 7.65–7.36 (m, 5H),
7.06–6.70 (m, 4H), 6.66–6.27 (m, 2H), 4.85–4.79 (m, 2H), 4.40–4.36 (m, 1H), 3.82 (s, 3H),
3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.0, 167.8, 160.4, 160.1, 134.4, 131.2,129.8,
129.6, 129.5, 128.3, 128.0, 124.7, 124.1, 114.2, 75.8, 69.2, 55.5, 55.4, 52.4; HRMS (ESI) m/z
479.1270 (M+H+), Calcd for C25H23N2O6S 479.1277. The ee was determined by HPLC
analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm) + CHIRALPAK ID-3 (4.6 mm i.d. x 250
mm); Hexane/2-propanol = 70/30; flow rate 1.0 mL/min; 25 oC; 254 nm; tR = 36.7 min (minor,
major diastereomer), 46.4 min (minor diastereomer), 52.3 min (major, major diastereomer),
65.5 min (minor diastereomer).
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(S)-3-(4-Methoxyphenyl)-5-((R)-2-nitro-1-(thiophen-2-yl)ethyl)-5-phenylthiazolidine-2,4-
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dione (7p), White solid; Mp 105.3–106.6 C; 74% ee; dr > 19:1; 41.3 mg (0.1 mmol), 91%
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yield; [α]2D2 +18.4 (c 1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 8.17–7.98 (m, 2H),
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7.62–7.37 (m, 4H), 7.34–7.20 (m, 1H), 7.09 (dd, J = 5.1, 3.6, 1H), 6.96–6.78 (m, 2H),
6.67–6.43 (m, 2H), 5.28 (dd, J = 11.3, 3.5, 1H), 4.74 (dd, J = 12.9, 11.4, 1H), 4.43 (dd, J =
13.0, 3.5, 1H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.9, 167.8, 160.2, 134.6, 133.8,
130.3, 130.0, 129.6, 128.3, 128.0, 127.2, 126.9, 124.7, 114.7, 68.9, 55.5, 49.5; HRMS (ESI)
m/z 455.0727 (M+H+), Calcd for C22H19N2O5S2 455.0735. The ee was determined by HPLC
analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0
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mL/min; 25 C; 254 nm; tR = 13.7 min (minor diastereomer), 22.8 min (minor diastereomer),
31.2 min (minor, major diastereomer), 35.3 min (major, major diastereomer).
(S)-5-((S)-1-Cyclohexyl-2-nitroethyl)-3-(4-methoxyphenyl)-5-phenylthiazolidine-2,4-dion
o
e (7q), White solid; Mp 126.0–127.2 C; 96% ee; dr = 5:1; 28.6 mg (0.1 mmol), 63% yield;
[α]2D2 –25.1 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.97–7.80 (m, 2H), 7.54–7.34 (m,
3H), 7.13–6.88 (m, 4H), 4.33–4.15 (m, 2H), 3.81 (s, 3H), 3.70–3.47 (m, 1H), 1.98–1.57 (m,
6H), 1.29–1.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 174.5, 169.2, 160.1, 135.8, 129.7,
129.4, 128.3, 127.8, 125.1, 114.8, 73.9, 69.1, 55.6, 50.5, 40.5, 33.8, 30.0, 27.1, 26.6, 25.8;
HRMS (ESI) m/z 455.1649 (M+H+), Calcd for C24H27N2O5S 455.1641. The ee was
determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol
= 90/10; flow rate 1.0 mL/min; 25 oC; 254 nm; tR = 12.8 min (minor diastereomer), 17.4 min
(major, major diastereomer), 18.9 min (minor, major diastereomer), 22.3 min (minor
diastereomer).
(S)-3-(4-Methoxyphenyl)-5-((S)-2-nitro-1-phenylethyl)-5-(p-tolyl)thiazolidine-2,4-dione
o
(7r), White solid; Mp 108.6–110.1 C; 90% ee; dr = 13:1; 41.1 mg (0.1 mmol), 89% yield;
[α]2D2 +21.6 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 8.4, 2H), 7.60–7.12
(m, 7H), 6.90–6.67 (m, 2H), 6.56–6.24 (m, 2H), 4.99–4.76 (m, 2H), 4.44–4.41 (m, 1H), 3.75
(s, 3H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.0, 167.7, 160.1, 140.0, 132.5, 131.3,
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130.2, 130.1, 129.4, 128.8, 128.3, 127.9, 124.9, 114.5, 75.7, 68.8, 55.5, 52.9, 21.0; HRMS
(ESI) m/z 463.1335 (M+H+), Calcd for C25H23N2O5S 463.1328. The ee was determined by
HPLC analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm) + CHIRALPAK ID-3 (4.6 mm i.d.
x 250 mm); Hexane/2-propanol = 70/30; flow rate 1.0 mL/min; 25 oC; 254 nm; tR = 29.1 min
(minor, major diastereomer), 45.5 min (minor diastereomer), 57.9 min (major, major
diastereomer), 82.4 min (minor diastereomer).
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(S)-5-(4-(tert-Butyl)phenyl)-3-(4-methoxyphenyl)-5-((S)-2-nitro-1-phenylethyl)thiazolidi
ne-2,4-dione (7s), White solid; Mp 108.6–110.2 oC; 87% ee; dr = 12:1; 43.8 mg (0.1 mmol),
87% yield; [α]2D2 +23.6 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J = 8.7, 2H),
7.61–7.37 (m, 7H), 6.87–6.68 (m, 2H), 6.51–6.21 (m, 2H), 5.05–4.74 (m, 2H), 4.46–4.43 (m,
1H), 3.75 (s, 3H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.0, 167.8, 160.2, 153.0,
132.5, 131.2, 130.1, 129.4, 128.8, 128.3, 127.7, 126.5, 124.7, 114.5, 75.7, 68.7, 55.5, 52.8,
34.7, 31.2; HRMS (ESI) m/z 505.1801 (M+H+), Calcd for C28H29N2O5S 505.1797. The ee
was determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. x 250 mm);
Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 oC; 254 nm; tR = 8.3 min (minor, major
diastereomer), 11.1 min (minor diastereomer), 13.7 min (major, major diastereomer), 41.3
min (minor diastereomer).
(S)-5-(Benzylthio)-3,5-diphenylthiazolidine-2,4-dione (9a), Colorless oil; 87% ee; 33.2 mg
(0.1 mmol), 85% yield; [α]2D2 –25.1 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J
= 7.3, 2H), 7.53–7.25 (m, 6H), 7.18 (dd, J = 17.3, 8.8, 7H), 4.00 (d, J = 11.8, 1H), 3.66 (d, J =
11.8, 1H); 13C NMR (75 MHz, CDCl3) δ 172.0, 167.8, 135.6, 134.8, 132.8, 129.5, 129.4,
129.4, 129.4, 129.2, 128.8, 127.7, 127.5, 127.4, 66.3, 37.6; HRMS (ESI) m/z 392.0780
(M+H+), Calcd for C22H18NO2S2 392.0779. The ee was determined by HPLC analysis.
CHIRALPAK IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min;
25 oC; 254 nm; tR = 12.8 min (minor), 20.0 min (major).
(S)-5-(Benzylthio)-3-(4-chlorophenyl)-5-phenylthiazolidine-2,4-dione (9b), Colorless oil; 88%
ee; 37.4 mg (0.1 mmol), 88% yield; [α]2D2 –20.8 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3)
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δ 7.63 (d, J = 7.4, 2H), 7.44–7.24 (m, 5H), 7.23–6.99 (m, 7H), 3.96 (d, J = 12.0, 1H), 3.65 (d,
J = 12.0, 1H); 13C NMR (75 MHz, CDCl3) δ 171.7, 167.6, 135.4, 135.3, 134.8, 131.1, 129.7,
129.5, 129.4, 129.2, 128.8, 128.7, 127.8, 127.5, 66.3, 37.7; HRMS (ESI) m/z 426.0390
(M+H+), Calcd for C22H17ClNO2S2 426.0389. The ee was determined by HPLC analysis.
CHIRALPAK IF (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min;
25 oC; 254 nm; tR = 8.0 min (minor), 10.4 min (major).
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(S)-5-(Benzylthio)-5-phenyl-3-(p-tolyl)thiazolidine-2,4-dione (9c), Colorless oil; 90% ee;
36.8 mg (0.1 mmol), 91% yield; [α]2D2 –21.9 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.66 (d, J = 7.4, 2H), 7.46–7.27 (m, 5H), 7.20–7.15 (m, 5H), 7.05 (d, J = 7.9, 2H), 4.00 (d, J =
13
11.8, 1H), 3.66 (d, J = 11.8, 1H), 2.31 (s, 3H); C NMR (75 MHz, CDCl3) δ 172.1, 167.9,
139.7, 135.7, 134.9, 130.2, 130.1, 129.4, 129.3, 129.2, 128.7, 127.7, 127.5, 127.1, 66.3, 37.6,
21.3; HRMS (ESI) m/z 406.0934 (M+H+), Calcd for C23H20NO2S2 406.0935. The ee was
determined by HPLC analysis. CHIRALPAK IF (4.6 mm i.d. x 250 mm); Hexane/2-propanol
= 80/20; flow rate 1.0 mL/min; 25 oC; 254 nm; tR = 10.2 min (minor), 12.6 min (major).
(S)-5-(Benzylthio)-3-(4-methoxyphenyl)-5-phenylthiazolidine-2,4-dione (9d), Colorless oil;
91% ee; 41.3 mg (0.1 mmol), 98% yield; [α]2D2 –24.2 (c 1.00, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.65 (d, J = 7.4, 2H), 7.42–7.23 (m, 3H), 7.22–6.99 (m, 7H), 6.91 (d, J = 8.3, 2H),
13
4.00 (d, J = 11.8, 1H), 3.70 (d, J = 17.5, 3H), 3.66 (d, J = 11.8, 1H); C NMR (75 MHz,
CDCl3) δ 172.2, 168.1, 160.2, 135.7, 134.9, 129.4, 129.4, 129.2, 128.8, 128.6, 127.7, 127.5,
125.4, 114.8, 66.2, 55.6, 37.6; HRMS (ESI) m/z 422.0884 (M+H+), Calcd for C23H20NO3S2
422.0885. The ee was determined by HPLC analysis. CHIRALPAK IF (4.6 mm i.d. x 250
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mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 C; 254 nm; tR = 11.6 min
(minor), 16.6 min (major).
(S)-5-(Benzylthio)-5-(4-(tert-butyl)phenyl)-3-(4-methoxyphenyl)thiazolidine-2,4-dione
(9e), Colorless oil; 87% ee; 39.6 mg (0.1 mmol), 83% yield; [α]2D2 –20.1 (c 1.00, CHCl3);1H
NMR (300 MHz, CDCl3) δ 7.67 (d, J = 7.7, 2H), 7.44 (d, J = 7.8, 2H), 7.26 (s, 5H), 7.19 (d, J
= 7.9, 2H), 7.02 (d, J = 8.1, 2H), 4.10 (d, J = 11.9, 1H), 3.85 (s, 3H), 3.80 (s, 1H), 1.35 (s, 9H);
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13C NMR (75 MHz, CDCl3) δ 172.3, 168.2, 160.2, 152.5, 135.1, 132.6, 129.4, 128.7, 128.6,
127.6, 127.2, 126.1, 125.5, 114.8, 66.2, 55.6, 37.6, 34.7, 31.2; HRMS (ESI) m/z 478.1517
(M+H+), Calcd for C27H28NO3S2 478.1511. The ee was determined by HPLC analysis.
CHIRALPAK IF (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min;
25 oC; 254 nm; tR = 9.3 min (minor), 11.5 min (major).
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(S)-5-(Benzylthio)-5-(4-chlorophenyl)-3-(4-methoxyphenyl)thiazolidine-2,4-dione
(9f),
Colorless oil; 88% ee; 40.0 mg (0.1 mmol), 88% yield; [α]2D2 –31.3 (c 1.00, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.60 (d, J = 8.2, 2H), 7.29 (d, J = 8.3, 2H), 7.28–6.94 (m, 7H), 6.92 (d, J
13
= 8.5, 2H), 3.99 (d, J = 12.0, 1H), 3.76 (s, 3H), 3.69 (d, J = 12.0, 1H); C NMR (75 MHz,
CDCl3) δ 171.9, 167.6, 160.2, 135.4, 134.7, 134.2, 129.3, 129.2, 129.0, 128.8, 128.5, 127.7,
125.3, 114.8, 65.6, 55.6, 37.7; HRMS (ESI) m/z 456.0492 (M+H+), Calcd for C23H19ClNO3S2
456.0495. The ee was determined by HPLC analysis. CHIRALPAK IF (4.6 mm i.d. x 250
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mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 C; 254 nm; tR = 15.0 min
(minor), 16.8 min (major).
(S)-5-(Benzylthio)-5-(3-fluorophenyl)-3-(4-methoxyphenyl)thiazolidine-2,4-dione
(9g),
Colorless oil; 89% ee; 41.7 mg (0.1 mmol), 95% yield; [α]2D2 –29.1 (c 1.00, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.41 (s, 2H), 7.29 (d, J = 7.7, 1H), 7.21–7.03 (m, 7H), 7.03–6.85 (m,
3H), 3.99 (d, J = 11.9, 1H), 3.75 (s, 3H), 3.69 (d, J = 11.9, 1H); 13C NMR (75 MHz, CDCl3) δ
171.8, 167.6, 162.8 (d, 1JC-F = 246.4 Hz), 160.2, 138.1 (d, 1JC-F = 7.3 Hz), 134.7, 130.7 (d,
1JC-F = 8.2 Hz), 129.3, 128.8, 128.5, 127.7, 125.2, 123.3 (d, 1JC-F = 3.0 Hz), 114.6 (d,
1JC-F = 21.0 Hz), 115.0 (d, 1JC-F = 24.2 Hz), 114.8, 65.4, 55.6, 37.7; HRMS (ESI) m/z
440.0791 (M+H+), Calcd for C23H19FNO3S2 440.0790. The ee was determined by HPLC
analysis. CHIRALPAK IF (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0
mL/min; 25 oC; 254 nm; tR = 10.4 min (minor), 12.8 min (major).
(S)-5-((4-Chlorobenzyl)thio)-3-(4-methoxyphenyl)-5-phenylthiazolidine-2,4-dione
(9h),
Colorless oil; 88% ee; 43.6 mg (0.1 mmol), 96% yield; [α]2D2 –30.2 (c 1.00, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.62 (d, J = 7.0, 2H), 7.31 (d, J = 6.8, 3H), 7.19–7.00 (m, 6H), 6.92 (d, J
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= 8.3, 2H), 3.94 (d, J = 12.3, 1H), 3.75 (s, 3H), 3.65 (d, J = 12.2, 1H); C NMR (75 MHz,
CDCl3) δ 172.2, 167.8, 160.2, 135.6, 133.6, 133.5, 130.7, 129.3, 129.2, 128.9, 128.5, 127.5,
125.3, 114.8, 66.0, 55.6, 37.0; HRMS (ESI) m/z 456.0490 (M+H+), Calcd for C23H19ClNO3S2
456.0495. The ee was determined by HPLC analysis. CHIRALPAK IF (4.6 mm i.d. x 250
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mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 C; 254 nm; tR = 13.1 min
(minor), 25.8 min (major).
(S)-3-(4-Methoxyphenyl)-5-((4-methylbenzyl)thio)-5-phenylthiazolidine-2,4-dione
(9i),
Colorless oil; 87% ee; 42.2 mg (0.1 mmol), 99% yield; [α]2D2 –10.0 (c 1.00, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.77 (d, J = 7.0, 2H), 7.44 (d, J = 7.9, 3H), 7.14 (dt, J = 16.1, 8.1, 6H),
7.02 (d, J = 7.5, 2H), 4.08 (d, J = 11.6, 1H), 3.85 (s, 3H), 3.75 (d, J = 11.9, 1H), 2.33 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 170.3, 166.2, 158.2, 135.5, 133.9, 129.7, 127.5, 127.4, 127.2,
126.7, 125.6, 123.5, 112.8, 64.4, 53.7, 35.4, 19.2; HRMS (ESI) m/z 436.1042 (M+H+), Calcd
for C24H22NO3S2 436.1041. The ee was determined by HPLC analysis. CHIRALPAK IF (4.6
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mm i.d. x 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 C; 254 nm; tR =
13.7 min (minor), 29.3 min (major).
(S)-3-(4-Methoxyphenyl)-5-((3-methylbenzyl)thio)-5-phenylthiazolidine-2,4-dione
(9j),
Colorless oil; 89% ee; 42.6 mg (0.1 mmol), 98% yield; [α]2D2 –19.4 (c 1.00, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.77 (d, J = 7.0, 2H), 7.52 – 7.34 (m, 3H), 7.20 (d, J = 8.8, 3H), 7.03 (d,
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J = 10.0, 5H), 4.08 (d, J = 11.7, 1H), 3.86 (s, 3H), 3.74 (d, J = 11.8, 1H), 2.31 (s, 3H); C
NMR (75 MHz, CDCl3) δ 170.3, 166.2, 158.2, 136.5, 133.8, 132.8, 128.2, 127.4, 127.2, 126.7,
126.7, 126.5, 125.6, 124.5, 123.5, 112.8, 64.4, 53.7, 35.6, 19.4; HRMS (ESI) m/z 436.1037
(M+H+), Calcd for C24H22NO3S2 436.1041. The ee was determined by HPLC analysis.
CHIRALPAK IF (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 mL/min;
25 oC; 254 nm; tR = 13.9 min (minor), 17.4 min (major).
(S)-3-(4-Methoxyphenyl)-5-phenyl-5-(phenylthio)thiazolidine-2,4-dione (9k), Colorless oil;
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12% ee; 32.5 mg (0.1 mmol), 80% yield; [α]D –5.1 (c 1.00, CHCl3); H NMR (300 MHz,
CDCl3) δ 7.86 (d, J = 7.2, 2H), 7.70 (d, J = 7.5, 2H), 7.60–7.33 (m, 6H), 6.88 (d, J = 8.5, 2H),
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