An asymmetric organocatalytic approach to Michael reactions of thiazolones and nitroalkenes: Preparation of compounds with anti-cancer potency

Article abstract of DOI:10.1002/ejoc.201201094

We present a highly efficient strategy for obtaining a series of chiral 2,4-disubstituted thiazolone derivatives with excellent diastereo-and enantioselectivities through the creation of carbon-and nitrogen-substituted quaternary carbon stereocenters. With the chiral tertiary amine-thiourea catalyst developed by our group, the reactions could be performed smoothly at 1 mol-% catalyst loadings without any additive. Preliminary biological evaluation demonstrated that these analogues could inhibit cell proliferation in vitro significantly.

Full text of DOI:10.1002/ejoc.201201094

FULL PAPER
DOI: 10.1002/ejoc.201201094
An Asymmetric Organocatalytic Approach to Michael Reactions of
Thiazolones and Nitroalkenes: Preparation of Compounds with Anti-Cancer
Potency
Xiaodong Liu,[a] Hongjin Song,[a] Qiao Chen,[a] Wenyi Li,[a] Wen Yin,[a] Ming Kai,[a] and
Rui Wang*[a]
Keywords: Organocatalysis / Asymmetric catalysis / Michael addition / Biological activity / Medicinal chemistry /
Antitumor agents
We present a highly efficient strategy for obtaining a series of
chiral 2,4-disubstituted thiazolone derivatives with excellent
diastereo- and enantioselectivities through the creation of
carbon- and nitrogen-substituted quaternary carbon stereo-
centers. With the chiral tertiary amine-thiourea catalyst de-
veloped by our group, the reactions could be performed
smoothly at 1 mol-% catalyst loadings without any additive.
Preliminary biological evaluation demonstrated that these
analogues could inhibit cell proliferation in vitro significantly.
membered heterocyclic structures in medicinal chemistry
has drawn special attention in the construction of their de-
rivatives. Although a number of synthetic strategies for the
synthesis of these thiazole derivatives have been developed,
especially for 2,4-disubstituted thiazole analogues, almost
all of these studies have until now been focused on the race-
mic forms.[6] Exploitation of new organocatalyst methodol-
ogies for the preparation of thiazole derivatives with drug
activities in enantiopure forms would therefore be an im-
portant advancement for expanding their pharmaceutical
usage.
Introduction
During the past decades, increasing comprehension of
the mechanism of drug interaction on a molecular level has
led to greatly increased awareness of the importance of chi-
rality as a key to the efficacy of many medicinal products.[1]
It is now well known that generally only one stereoisomer
of a pharmaceutical is required for efficacy and that other
stereoisomers are either inactive or exhibit considerably re-
duced activities. Accordingly, many new drugs in clinical
use and under development consist of single optically active
isomers to avoid the possibility of side effects due to unde-
sirable stereoisomers.[2]
Thiazole heterocyclic systems are ubiquitous in numer-
ous natural molecules that have been isolated and shown to
exhibit significant pharmaceutical activities.[3] The thiazol-
idinone moiety, for instance, is known to be associated with
antibiotic, immunosuppressive, and antitumor properties
and so has come to occupy a prominent position in the
drug discovery process.[4] Moreover, a number of naturally
occurring molecules containing the aminothiazole ring
structure have been applied in several drugs marketed for
the treatment of HIV infection, hypertension, and inflam-
mation (Figure 1).[5] The established utility of these five-
Figure 1. Examples of pharmaceuticals containing thiazole ring
moieties.
[a] Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, School of Basic Medical Science, Institute of
Biochemistry and Molecular Biology School of Life Science,
Lanzhou University,
In 2010, some asymmetric examples of the use of 2-
(benzyloxy)thiazol-5(4H)-ones in catalytic synthesis were
reported by Ooi’s group, who used a C1-symmetric chiral
ammonium betaine as catalyst and obtained high stereose-
lectivities.[7] Subsequently, an organocatalytic approach for
the preparation of chiral 2-(ethylthio)thiazolone adducts,
Lanzhou 730000, P.R. China
Fax: +86-931-891-2567
E-mail: wangrui@lzu.edu.cn
Homepage: http://jchyxy.lzu.edu.cn/lzupage/2009/10/29/
N20091029172604.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201094.
Eur. J. Org. Chem. 2012, 6647–6655
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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X. Liu, H. Song, Q. Chen, W. Li, W. Yin, M. Kai, R. Wang
FULL PAPER
several of which were found to show potential anticancer Table 1. Initial reaction optimization.[a]
activities, was developed by our group.[8] Consequently, we
believed that optically active addition products of other
electrophilic reagents with thiazolones might also be at-
tractive. Because of the easy transformations that allow fur-
ther reactions based on the nitro functionality, we demon-
strate here a new organocatalytic approach using nitroalk-
enes as electrophilic reagents to react with racemic 2,4-di-
substituted thiazolones, a previously little-studied field.
These reactions led efficiently, in one-step manner, to a
series of chiral 2,4-disubstituted thiazolone derivatives
(CDTDs) each containing two new chiral centers.
Entry Catalyst (10 mol-%)
T [°C] Solvent
t [h] dr (% ee)
Results and Discussion
1
quinine
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
solvent
anisole
MTBE
MTBE
MTBE
MTBE
6
6
5:1 (33)
4:1 (0)
To achieve the desired enantioselective conjugate ad-
dition, reactions between 2,4-disubstituted thiazolones and
nitroalkenes in the presence of various organocatalysts and
solvents were investigated (Table 1). We hoped to take the
advantage of what we had learned from the reactions be-
tween N-tosyl aldimines and 2-(ethylthio)thiazolones; initial
results were not encouraging, however, because the quin-
idine catalyst gave the adduct 3a in racemic form (Entry 2),
whereas use of quinine and TMSQ as catalysts separately
gave 33% and 13% ee values (Entries 1 and 3). During the
course of optimization, it was found that the bifunctional
thiourea-tertiary amine 4a, which performed deficiently in
the Mannich addition, could afford the adduct 3a with a
good diastereomeric ratio and a 73% ee (Entry 4). Use of
urea catalyst 4b, with the same configuration, resulted in
dramatic decreases in stereoselectivities, probably as the re-
sult of decreased hydrogen bonding (Entry 5). Finally, we
used thiourea catalysts 4c and 4d, with bulky groups, which
were developed by our group.[9] It was found that both per-
formed well, with 4d giving the best result (Entries 6 and
7).
2
3
4
quinidine
TMSQ[b]
4a
6
6
8
5
5
5
8
5
4:1 (13)
5:1 (73)
4:1 (–11)
3:1 (81)
5:1 (89)
6:1 (86)
4:1 (85)
5:1 (92)
5:1 (94)
4:1 (92)
Ͻ4:1 (84)
5
4b
6
4c
7
4d
4d
4d
8[c]
9
10
11
12
13[d]
4d
4d
4d
4d
6
18
36
–40
–80
[a] Unless indicated otherwise, all reactions were performed with
1a (0.10 mmol) and 2a (0.15 mmol) in solvent (1.0 mL) for 5–8 h,
and full conversion was observed in all cases. Dr values were deter-
mined by 1H NMR measurements before purification; ee values
were determined by chiral HPLC on a Chiralpak OD column.
[b] TMSQ is quinine with a TMS protecting group. [c] The solvent
was cyclohexyl methyl ether. [d] The level of conversion of the reac-
tant was under 70% after 36 h.
substrate 1l gave the best result: the corresponding adduct
Subsequently the effects of different solvents were investi- 3l was obtained in good yield with a 10:1 dr and a 96% ee
gated; MTBE proved to be optimal (Entries 8–10). With the value (Entry 12). A somewhat longer reaction time was re-
goal of improving the enantioselectivity further, we con- quired for a 2,5-dimethoxy-substituted nitroalkene (En-
ducted a cursory examination of the influence of the reac- try 19), due to its inherently lower reactivity toward nucleo-
tion temperature. When the reaction temperature was low- philes, but it still gave excellent results.
ered to 0 °C, a higher ee value of 94% with a maintained
The additions of more sterically hindered 1-naphthyl-
diastereomeric ratio was achieved (Entry 11). Further cool- and 2-naphthyl-derived nitroalkenes proceeded equally well,
ing resulted in longer reaction time and decreased stereose- with excellent enantioselectivities and good diastereoselec-
lectivities. Under –80 °C, the level of conversion of 1a was tivities (Entries 20 and 21). Heteroaromatic nitroolefins
still under 70% after 36 h (Entry 13).
were also viable substrates (Entries 22 and 23). With alkyl
With the optimized condition established, we explored nitroalkenes the reactivity was less, and so we utilized alk-
the scope of the enantioselective additions between 2,4-di- enyl-substituted nitroalkene 1x as the synthetic equivalent
substituted thiazolones and nitroalkenes in the presence of of alkyl nitroalkenes in Entry 24. The reaction was per-
4d (10 mol-%) at 0 °C, as shown in Table 2. Of the reactions formed for 12 h and selectively gave adduct 3x with moder-
with the 2,4-disubstituted thiazolone 2a as nucleophile, the ate results.
majority proceeded smoothly to furnish the corresponding
Furthermore, several different substituted 2,4-disubsti-
masked CDTDs in moderate to good yields and with excel- tuted thiazolones were evaluated and also found to be good
lent diastereo- and enantioselectivities. The aromatic nitro- substrates for this method (Entries 26–28). A high enantio-
alkenes tolerated substitutions at any position in their aro- selectivity (92%) with a moderate diastereomeric ratio (4:1)
matic rings, and both electron-donating and electron-with- was observed when the 2,4-disubstituted thiazolone had a
drawing functionalities were compatible (Entries 1–18). The benzyl substituent at the R5 position. A longer reaction
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Asymmetric Organocatalytic Michael Addition
Table 2. Scope of the reaction.[a]
Entry R3, R4, R5
3, t [h], % yield[b] dr (% ee)
1[c]
2
Ph, iPr, Et
2-F-Ph, iPr, Et
3a, 6, 81 (80)
3b, 8, 87
5:1 (94) (5:1, 92)
9:1 (95)
3[c]
4[c]
5[c]
6[c]
7[c]
8
4-F-Ph, iPr, Et
3c, 8, 74 (63)
3d, 6, 83 (69)
3e, 6, 83 (71)
3f, 10, 82 (67)
3g, 6, 84 (75)
3h, 8, 70
3i, 8, 87
3j, 6, 65
3k, 6, 83
3l, 6, 84 (76)
3m, 8, 79
3n, 8, 73
3o, 8, 64
3p, 8, 75 (71)
3q, 6, 71
3r, 6, 83
8:1 (93) (8:1, 91)
9:1 (96) (9:1, 95)
8:1 (94) (8:1, 91)
8:1 (94) (7:1, 93)
7:1 (94) (7:1, 92)
7:1 (94)
6:1 (94)
7:1 (90)
8:1 (92)
10:1 (96) (9:1, 95)
6:1 (93)
5:1 (92)
9:1 (96)
8:1 (91) (9:1, 90)
7:1 (94)
9:1 (92)
2-Cl-Ph, iPr, Et
3-Cl-Ph, iPr, Et
4-Cl-Ph, iPr, Et
2-Br-Ph, iPr, Et
3-Br-Ph, iPr, Et
4-Br-Ph, iPr, Et
2-Me-Ph, iPr, Et
4-Me-Ph, iPr, Et
2-NO2-Ph, iPr, Et
3-NO2-Ph, iPr, Et
4-NO2-Ph, iPr, Et
3-MeO-Ph, iPr, Et
4-MeO-Ph, iPr, Et
4-CN-Ph, iPr, Et
3,4- (Me)2-Ph, iPr, Et
9[c]
10
11
Figure 2. X-ray structure of the adduct 3i.
12[c]
13
14
15
phatic substituent at the R4 position had little influence on
the cytotoxic activities. However, the activities of the com-
pounds decreased when a benzyl substituent was present at
the R5 position. We can conclude that the nitro function-
ality is an important candidate for the cytotoxic activities
of CDTDs and that the modification of substituents R3 and
R5 can further improve their activities in the presence of
the nitro group.
Conversion of the nitro groups in adducts 3 into primary
amine groups might improve the compounds’ water-solubil-
ities and bioavailabilities, due to the hydrogen-bonding in-
teraction between the primary amine group and the oxo
group, so we prepared chiral derivatives 5a and 5b
(Scheme 1), containing primary amine groups, in 78% and
82% yields, respectively. Compound 5a could also be easily
converted into compound 6a with retention of diastereo-
selectivity and enantioselectivity. Unfortunately, the cyto-
16[c]
17
18
19
2,5- (MeO)2-Ph, iPr, Et 3s, 24, 71
9:1 (96)
3:1 (92) (3:1, 92)
6:1 (83)
4:1 (88/83)
5:1 (87)
1:4 (97/70)
nd (nd)
3:1 (80)
9:1 (84)
4:1 (92)
20[c]
21
1-naphthyl, iPr, Et
2-naphthyl, iPr, Et
2-furyl, iPr, Et
3t, 12, 64 (60)
3u, 36, 82
3v, 12, 93
3w, 36, 80
22[d]
23
2-thienyl, iPr, Et
24[d]
25[e]
26
(E)-Ph-CH=CH-, iPr, Et 3x, 12, 66
cyclohexyl, iPr, Et
2-NO2-Ph, iBu, Et
4-CN-Ph, tBu, Et
4-CN-Ph, iPr, Bn
–, 48, –
3y, 8, 62
3z, 18, 68
3zЈ, 12, 71
27
28
[a] For experimental details, see the Supporting Information.
[b] Isolated yields. [c] The reactions were also performed with
0.001 mmol of 4d; results are shown in brackets. [d] The yields of
both diastereoisomers. [e] Under the optimized conditions, the sub-
strate 1y showed no reactivity toward 2-(ethylthio)thiazolone 2a.
time was required for substrate 2c, presumably due to steric toxic activities exhibited loss on PC-3 cells, the inhibition
hindrance of the tertiary butyl group at the R4 position of growth decreased from 56% (with 3p) to 23% (with 5a)
(Entry 27).
and 61% (with 3m) to 22% (with 5b) separately when the
The relative and absolute configurations of the products chiral adducts 5 were used. It was concluded that the nitro
were determined with the aid of an X-ray crystal structure groups played a positive role in the cytotoxic activities of
analysis of 3i (Figure 2).[10]
these analogues.
In view of the case in which we had obtained a series of
Because we had demonstrated that the CDTDs displayed
CDTDs, we decided to evaluate the compounds’ anticancer significant cytotoxic activities, we decided to explore the
activities. Using a colorimetric 3-(4,5-dimethylthiazol-2-yl)- potential of this reaction for practical application further.
2,5-diphenyltetrazolium bromide (MTT) assay, we investi- Firstly, we tested the additions between 2,4-disubstituted
gated cytotoxic activities against five human cancer cell thiazolones and nitroalkenes at 1 mol-% catalyst loading to
lines (T-24, PC-3, MDA-MB-231, HeLa, and HepG-2); a evaluate the potential of the catalyst 4d. To our delight,
summary of the IC50 values is shown in Table 3. In sharp the majority of the adducts were obtained with maintained
contrast to compounds derived from N-tosyl aldimines, the diastereoselectivities and only slightly decreased enantio-
analogues derived from nitroalkenes exhibited significant selectivities, albeit with generally prolonged reaction times
increases in cytotoxic activities. In experiments in which a and slightly reduced yields (Table 2, data in brackets in En-
1-naphthyl substituent was present at the R3 position of tries 1, 3–7, 12, 16, and 20). A reaction was then carried
the compound, exciting IC50 values were found with all the out on a gram scale, and an adduct was obtained with a
cancer cells, in particular with 3.52 μm in the HeLa cell. The perfect enantioselectivity (Ͼ99% ee value) and only slightly
IC50 values also showed that the replacement of the ali- decreased diastereoselectivity (Scheme 2).
Eur. J. Org. Chem. 2012, 6647–6655
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6649

X. Liu, H. Song, Q. Chen, W. Li, W. Yin, M. Kai, R. Wang
FULL PAPER
Table 3. IC50 values of CDTDs on the growth of human cancer cell through asymmetric organocatalysis in Michael reactions.
lines.[a]
The additions of thiazolones to nitroalkenes were catalyzed
by the tertiary amine-thiourea catalyst developed by our
group. Under mild conditions, the reactions could be per-
formed efficiently with catalyst loadings as low as 1 mol-%
without any additive. These new derivatives were found to
show high inhibitory effects on the viabilities of five types
of cancer cells in vitro. This preliminary study might pro-
vide a basic strategy for the further development of new
chiral heterocycle compounds with anti-cancer potency.
Entry
Adduct MDA-MB-231 T-24
HeLa HepG-2 PC-3
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
23.03
30.58
16.39
26.72
31.29
13.98
19.75
26.43
20.64
17.24
27.17
15.17
20.36
10.23
16.71
18.13
13.11
15.4
20.94 19.06 28.26
35.19
26.73
20.01
13.75
16.01
17.83
11.31
11.63
17.42
17.23
12.72
14.11
11.6
19.48 14.74 19.78
17.46 17.25 29.84
17.21 13.89 18.16
17.66 8.29
22.17
12.17 12.24 15.72
16.43 13.73 18.94
12.28 32.15 17.73
22.95 20.82 19.87
21.81 15.55 21.76
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Experimental Section
9.48
10.62 15.18
13.83 10.02 20.04
15.09 15.83 15.69
15.42 16.4
17.28 11.04 20.53
11.23 10.38 18.78
23.72 14.13 19.89
General Procedure for the Additions between 2,4-Disubstituted Thi-
azolones and Nitroalkenes: A nitroalkene 1 (0.10 mmol) was added
at 0 °C to a mixture of a 2,4-disubstituted thiazolone 2 (0.15 mmol)
and catalyst 4d (0.01 mmol/0.001 mmol) in MTBE (1.0 mL). After
the reaction was complete (as determined by TLC), the reaction
mixture was concentrated, and the residue was purified by flash
chromatography (petroleum ether/ethyl acetate 9:1) to afford the
product 3.
22.54
19.21
13.56
12.73
22.34
7.11
3t
6.14
4.17
24.91 22.84 35.15
8.72 6.67 15.577
13.26 13.07 18.51
17.86 14.64 20.5
3.52
8.05
3w
3y
3z
3zЈ
37.48
13.46
15.34
29.97
39.69
11.79
13.14
16.5
Cytotoxicity Assay: The modified colorimetric 3-(4,5-dimethylthi-
azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma–Aldrich)
assay is a widely used “in vitro’ assay for quantifying cell prolifera-
tion and viability that determines reduction in cell viability on the
basis of reduction of the tetrazolium salt by actively growing cells
to produce a blue formazan product. The MTT test was performed
as described previously, with some modifications. Briefly, cells
(5000 cells per well) were cultured in 96-well plates (Costar) for
24 h. The old culture medium was replaced with fresh, and the cells
were incubated with various concentrations of compounds for an
additional 48 h. After this period of time, the MTT stock solution
(5 mgmL–1 in PBS) was added to each well and incubation was
carried out at 37 °C for 4 h. 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
with a Bio-Rad Model 680 microplate reader. Experiments were
performed in duplicate and repeated at least three times. The IC50
value was calculated from the semi-logarithmic dose–response
curves.
[a] Values were means of three experiments, each done in duplicate.
IC50 values are expressed in μm. MDA, T-24, HeLa, HepG-2, and
PC-3 cells were seeded at a density of 5000 cellsmL–1 in 96-well
plates. Compounds were added 24 h after seeding. After 2 d in cul-
ture, the MTT stock solution (5 mgmL–1 in PBS) was added to
each well and the mixture was incubated at 37 °C for 4 h. The me-
dium was removed carefully, and dimethyl sulfoxide was added to
each well to dissolve formazan. The absorbance of each well at
490 nm was measured with a Bio-Rad Model 680 microplate
reader.
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-2-nitro-1-phenylethyl]thiazol-
5(4H)-one: Compound 3a was isolated by column chromatography
on silica gel as a single diastereoisomer in 81% yield (28.6 mg, dia-
stereomeric ratio 5:1), or in 80% yield (28.2 mg, diastereomeric ra-
tio 5:1) when 1 mol-% 4d was used. White solid; m.p. 108–109 °C.
Scheme 1. Transformations of the products. Reagents and condi-
tions: i) SnCl2, concd. HCl, EtOH, room temp.; ii) (Boc)2O, Et3N,
THF, room temp.
1
[α]2D0 = +23.3 (c = 2.49 in CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.39–7.31 (m, 2 H), 7.29 (dd, J = 6.5, 3.3 Hz, 3 H), 4.92 (dd, J
= 12.8, 11.9 Hz, 1 H), 4.64 (dd, J = 13.0, 3.7 Hz, 1 H), 4.18 (dd, J
= 11.8, 3.7 Hz, 1 H), 3.34–3.06 (m, 2 H), 2.22–2.05 (m, 1 H), 1.42
(t, J = 7.4 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.7 (s), 162.1 (s),
134.4 (s), 129.4 (s), 128.3 (s), 92.9 (s), 75.6 (s), 48.4 (s), 34.3 (s),
25.4 (s), 17.1 (s), 16.3 (s), 14.7 (s) ppm. IR (CDCl ): ν = 2972, 1718,
˜
3
Scheme 2. Preparative-scale experiment.
1559, 1456, 1378, 1265, 973, 849, 753, 702 cm–1. HRMS (ESI):
calcd. for [C16H20N2O3S2 + H]+ 353.0988; found 353.0981. HPLC
(Chiralpak OD-H column, n-hexane/iPrOH 90:10, flow rate
1.0 mLmin–1, retention time: tmajor = 7.5, tminor = 9.7, 94% ee).
Conclusions
(S)-2-(Ethylthio)-4-[(S)-1-(2-fluorophenyl)-2-nitroethyl]-4-isopropyl-
thiazol-5(4H)-one: Compound 3b was isolated by column
chromatography on silica gel as a single diastereoisomer in 87%
In summary, we report the synthesis of optically active
2,4-disubstituted thiazolone derivatives with high levels of
enantio- and diastereoselectivity (up to 96% ee and 10:1 dr) yield (32.3 mg, diastereomeric ratio 9:1). White solid; m.p. 104–105
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Asymmetric Organocatalytic Michael Addition
°C. [α]2D0 = +38.8 (c = 2.06 in CHCl3). 1H NMR (300 MHz,
75.2 (s), 47.9 (s), 34.3 (s), 25.4 (s), 17.1 (s), 16.3 (s), 14.7 (s) ppm.
CDCl3): δ = 7.42 (t, J = 7.3 Hz, 1 H), 7.32–7.21 (m, 1 H), 7.14– IR (CDCl ): ν = 2972, 1717, 1559, 1472, 1377, 1082, 974, 697 cm–1.
˜
3
6.95 (m, 2 H), 4.95 (t, J = 12.9 Hz, 1 H), 4.72 (dd, J = 13.6, 3.6 Hz,
HRMS (ESI): calcd. for [C16H19ClN2O3S2 + H]+ 387.0598; found
2 H), 3.26 (tt, J = 14.7, 7.4 Hz, 1 H), 3.17–3.01 (m, 1 H), 2.28–2.06 387.0593. HPLC (Chiralpak OD-H column, n-hexane/iPrOH
(m, 1 H), 1.39 (t, J = 7.4 Hz, 3 H), 1.18 (d, J = 6.8 Hz, 3 H), 0.90 90:10, flow rate 1.0 mLmin–1, retention time: tmajor = 5.6, tminor
=
(d, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.9 6.5, 94% ee).
(s), 162.8 (s), 162.0 (s), 159.5 (s), 130.1 (d, J = 8.6 Hz), 124.2 (d, J
= 3.5 Hz), 121.8 (d, J = 13.5 Hz), 115.9 (s), 115.6 (s), 92.9 (s), 74.6
(S)-4-[(S)-1-(4-Chlorophenyl)-2-nitroethyl]-2-(ethylthio)-4-isopropyl-
thiazol-5(4H)-one: Compound 3f was isolated by column
chromatography on silica gel as a single diastereoisomer in 82%
yield (31.7 mg, diastereomeric ratio 8:1), or in 67% yield (25.9 mg,
diastereomeric ratio 7:1) when 1 mol-% 4d was used. White solid;
m.p. 61–62 °C. [α]2D0 = +16.8 (c = 2.08 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.33–7.23 (m, 5 H), 4.86 (dd, J = 13.0,
11.9 Hz, 1 H), 4.62 (dd, J = 13.1, 3.8 Hz, 1 H), 4.16 (dd, J = 11.8,
3.8 Hz, 1 H), 3.33–3.04 (m, 2 H), 2.09 (dq, J = 13.5, 6.8 Hz, 1 H),
1.42 (t, J = 7.4 Hz, 3 H), 1.09 (d, J = 6.8 Hz, 3 H), 0.90 (d, J =
6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.4 (s), 162.6
(s), 134.4 (s), 132.7 (s), 130.7 (s), 128.6 (s), 92.7 (s), 75.4 (s), 47.7
(s), 34.5 (s), 25.3 (s), 17.3 (s), 16.6 (s), 14.6 (s) ppm. IR (CDCl ): ν
˜
3
= 2972, 1719, 1559, 1493, 1377, 1233, 1108, 973, 759 cm–1. HRMS
(ESI): calcd. for [C16H19FN2O3S2 + H]+ 371.0894; found 371.0887.
HPLC (Chiralpak OD-H column, n-hexane/iPrOH 90:10, flow rate
1.0 mLmin–1, retention time: tmajor = 5.8, tminor = 6.9, 95% ee).
(S)-2-(Ethylthio)-4-[(S)-1-(4-fluorophenyl)-2-nitroethyl]-4-isopropyl-
thiazol-5(4H)-one: Compound 3c was isolated by column
chromatography on silica gel as a single diastereoisomer in 74%
yield (27.4 mg, diastereomeric ratio 8:1), or in 63% yield (23.3 mg,
diastereomeric ratio 8:1) when 1 mol-% 4d was used. White solid;
m.p. 93–94 °C. [α]2D0 = +17.7 (c = 1.07 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.40–7.28 (m, 2 H), 6.98 (t, J = 8.7 Hz, 2
H), 4.97–4.79 (m, 1 H), 4.64 (dd, J = 13.0, 3.8 Hz, 1 H), 4.17 (dd,
J = 11.9, 3.8 Hz, 1 H), 3.36–3.05 (m, 2 H), 2.11 (hept, J = 6.7 Hz,
1 H), 1.42 (t, J = 7.4 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 3 H), 0.90 (d,
J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.6 (s),
164.2 (s), 162.5 (s), 160.9 (s), 131.0 (d, J = 8.3 Hz), 129.9 (d, J =
3.4 Hz), 115.5 (s), 115.2 (s), 92.9 (s), 75.6 (s), 47.6 (s), 34.3 (s), 25.4
(s), 34.3 (s), 25.4 (s), 17.0 (s), 16.2 (s), 14.6 (s) ppm. IR (CDCl ): ν
˜
3
= 2971, 1718, 1558, 1492, 1377, 973, 753 cm–1. HRMS (ESI): calcd.
for [C16H19ClN2O3S2 + H]+ 387.0598; found 387.0576. HPLC
(Chiralpak OD-H column, n-hexane/iPrOH 90:10, flow rate
1.0 mLmin–1, retention time: tmajor = 6.1, tminor = 7.6, 93% ee).
(S)-4-[(S)-1-(2-Bromophenyl)-2-nitroethyl]-2-(ethylthio)-4-isopropyl-
thiazol-5(4H)-one: Compound 3g was isolated by column
chromatography on silica gel as a single diastereoisomer in 84%
yield (36.2 mg, diastereomeric ratio 7:1), or in 75% yield (32.3 mg,
diastereomeric ratio 7:1) when 1 mol-% 4d was used. White solid;
m.p. 100–101 °C. [α]2D0 = –3.8 (c = 1.84 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.54 (dd, J = 8.0, 1.3 Hz, 1 H), 7.40 (dd,
J = 7.8, 1.6 Hz, 1 H), 7.30–7.21 (m, 1 H), 7.12 (td, J = 7.7, 1.7 Hz,
1 H), 5.10 (dd, J = 11.3, 3.7 Hz, 1 H), 5.02–4.90 (m, 1 H), 4.81
(dd, J = 13.0, 3.7 Hz, 1 H), 3.35 (tt, J = 14.7, 7.3 Hz, 1 H), 3.12–
2.97 (m, 1 H), 2.25 (hept, J = 6.6 Hz, 1 H), 1.36 (t, J = 7.4 Hz, 3
H), 1.31 (d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 212.0 (s), 161.2 (s), 134.2 (s), 133.3
(s), 129.7 (s), 128.0 (s), 127.4 (d, J = 14.0 Hz), 93.3 (s), 75.0 (s), 45.9
(s), 17.1 (s), 16.3 (s), 14.7 (s) ppm. IR (CDCl ): ν = 2973, 1722,
˜
3
1559, 1511, 1378, 1231, 974, 823, 660 cm–1. HRMS (ESI): calcd.
for [C16H19FN2O3S2 + H]+ 371.0894; found 371.0889. HPLC (Chi-
ralpak OD-H column, n-hexane/iPrOH 90:10, flow rate
1.0 mLmin–1, retention time: tmajor = 5.6, tminor = 7.0, 92% ee).
(S)-4-[(S)-1-(2-Chlorophenyl)-2-nitroethyl]-2-(ethylthio)-4-isopropyl-
thiazol-5(4H)-one: Compound 3d was isolated by column
chromatography on silica gel as a single diastereoisomer in 83%
yield (32.1 mg, diastereomeric ratio 9:1), or in 69% yield (26.7 mg,
diastereomeric ratio 9:1) when 1 mol-% 4d was used. White solid;
m.p. 109–110 °C. [α]2D0 = +2.79 (c = 1.43 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.49–7.40 (m, 1 H), 7.35 (dt, J = 7.3,
3.7 Hz, 1 H), 7.24–7.16 (m, 2 H), 5.09 (dd, J = 11.3, 3.7 Hz, 1 H),
4.94 (t, J = 12.2 Hz, 1 H), 4.79 (dd, J = 13.0, 3.7 Hz, 1 H), 3.41–
3.17 (m, 1 H), 3.05 (dq, J = 14.7, 7.4 Hz, 1 H), 2.23 (dt, J = 13.8,
6.9 Hz, 1 H), 1.36 (t, J = 7.4 Hz, 3 H), 1.26 (t, J = 6.4 Hz, 4 H),
0.88 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
211.8 (s), 161.4 (s), 136.1 (s), 132.6 (s), 130.0 (s), 129.4 (s), 128.1
(s), 126.9 (s), 93.4 (s), 75.1 (s), 60.4 (s), 43.1 (s), 34.7 (s), 25.2 (s),
(s), 34.7 (s), 25.2 (s), 17.5 (s), 17.0 (s), 14.6 (s) ppm. IR (CDCl ): ν
˜
3
= 2971, 1715, 1559, 1467, 1377, 972, 754 cm–1. HRMS (ESI): calcd.
for [C16H19BrN2O3S2 + H]+ 431.0093; found 431.0080. HPLC
(Chiralpak OD-H column, n-hexane/iPrOH 90:10, flow rate
1.0 mLmin–1, retention time: tmajor = 6.5, tminor = 7.4, 94% ee).
(S)-4-[(S)-1-(3-Bromophenyl)-2-nitroethyl]-2-(ethylthio)-4-isopropyl-
thiazol-5(4H)-one: Compound 3h was isolated by column
chromatography on silica gel as a single diastereoisomer in 70%
yield (30.2 mg, diastereomeric ratio 7:1). White solid; m.p. 105–107
17.4 (s), 16.9 (s), 14.6 (s) ppm. IR (CDCl ): ν = 2971, 1715, 1558,
˜
3
1471, 1376, 1207, 1038, 971, 754 cm–1. HRMS (ESI): calcd. for
[C16H19ClN2O3S2 + H]+ 387.0698; found 387.0606. HPLC (Chi-
ralpak OD-H column, n-hexane/iPrOH 90:10, flow rate
1.0 mLmin–1, retention time: tmajor = 6.1, tminor = 6.9, 96% ee).
1
°C. [α]2D0 = –3.8 (c = 0.8 in CHCl3); H NMR (300 MHz, CDCl3):
δ = 7.55 (s, 1 H), 7.43 (ddd, J = 7.9, 1.9, 1.1 Hz, 1 H), 7.34–7.22
(m, 1 H), 7.16 (t, J = 7.8 Hz, 1 H), 4.87 (dd, J = 13.2, 11.8 Hz, 1
H), 4.64 (dd, J = 13.2, 3.7 Hz, 1 H), 4.15 (dd, J = 11.8, 3.7 Hz, 1
H), 3.35–3.09 (m, 2 H), 2.12 (hept, J = 6.6 Hz, 1 H), 1.45 (t, J =
7.4 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.3 (s), 162.7 (s), 136.5
(s), 132.9 (s), 131.5 (s), 129.9 (s), 127.5 (s), 122.3 (s), 92.6 (s), 75.2
(s), 47.8 (s), 34.2 (s), 25.5 (s), 17.1 (s), 16.3 (s), 14.7 (s) ppm. IR
(S)-4-[(S)-1-(3-Chlorophenyl)-2-nitroethyl]-2-(ethylthio)-4-isopropyl-
thiazol-5(4H)-one: Compound 3e was isolated by column
chromatography on silica gel as a single diastereoisomer in 83%
yield (32.1 mg, diastereomeric ratio 8:1), or in 71% yield (27.4 mg,
diastereomeric ratio 8:1) when 1 mol-% 4d was used. White solid;
m.p. 90–91 °C. [α]2D0 = +4.2 (c = 1.9 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.39 (s, 1 H), 7.31–7.17 (m, 3 H), 4.87 (dd,
J = 13.1, 11.8 Hz, 1 H), 4.64 (dd, J = 13.2, 3.7 Hz, 1 H), 4.16 (dd,
J = 11.8, 3.7 Hz, 1 H), 3.36–3.10 (m, 2 H), 2.21–2.02 (m, 1 H), 1.44
(t, J = 7.4 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 6.7 Hz,
(CDCl ): ν = 2972, 1716, 1559, 1471, 1377, 1201, 1072, 974, 785,
˜
3
697 cm–1. HRMS (ESI): calcd. for [C16H19BrN2O3S2 + H]+
431.0093; found 431.0099. HPLC (Chiralpak OD-H column, n-
hexane/iPrOH 90:10, flow rate 1.0 mLmin–1, retention time: tmajor
= 6.2, tminor = 7.1, 94% ee).
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.4 (s), 162.7 (s), (S)-4-[(S)-1-(4-Bromophenyl)-2-nitroethyl]-2-(ethylthio)-4-isopropyl-
136.3 (s), 134.1 (s), 129.9 (s), 129.6 (s), 128.6 (s), 127.2 (s), 92.6 (s), thiazol-5(4H)-one: Compound 3i was isolated by column
Eur. J. Org. Chem. 2012, 6647–6655
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6651

X. Liu, H. Song, Q. Chen, W. Li, W. Yin, M. Kai, R. Wang
FULL PAPER
chromatography on silica gel as a single diastereoisomer in 87%
yield (37.5 mg, diastereomeric ratio 6:1). White solid; m.p. 71–72
°C. [α]2D0 = +8.97 (c = 3.23 in CHCl3). 1H NMR (300 MHz,
(CDCl ): ν = 2972, 1716, 1558, 1446, 1354, 973, 852, 664 cm–1.
˜
3
HRMS (ESI): calcd. for [C16H19N3O5S2 + H]+ 398.0839; found
398.0844. HPLC (Chiralpak OD-H column, n-hexane/iPrOH
CDCl3): δ = 7.42 (t, J = 5.4 Hz, 2 H), 7.30–7.19 (m, 2 H), 4.85 (dd, 90:10, flow rate 1.0 mLmin–1, retention time: tmajor = 9.9, tminor
=
J = 13.0, 11.9 Hz, 1 H), 4.62 (dd, J = 13.1, 3.8 Hz, 1 H), 4.15 (dd,
J = 11.8, 3.8 Hz, 1 H), 3.33–3.06 (m, 2 H), 2.10 (hept, J = 6.7 Hz,
1 H), 1.42 (t, J = 7.4 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 0.90 (d,
J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.3 (s),
162.6 (s), 133.3 (s), 131.5 (s), 131.0 (s), 122.5 (s), 92.6 (s), 75.4 (s),
47.8 (s), 34.3 (s), 25.4 (s), 17.0 (s), 16.2 (s), 14.6 (s) ppm. IR
11.8, 96% ee).
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-2-nitro-1-(3-nitrophenyl)ethyl]-
thiazol-5(4H)-one: Compound 3m was isolated by column
chromatography on silica gel as a single diastereoisomer in 79%
yield (31.4 mg, diastereomeric ratio 6:1). White solid; m.p. 86–87
°C. [α]2D0 = –20.1 (c = 1.94 in CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 8.41 (s, 1 H), 8.18 (ddd, J = 8.2, 2.3, 1.0 Hz, 1 H), 7.73–7.62
(m, 1 H), 7.50 (t, J = 8.0 Hz, 1 H), 4.91 (dd, J = 13.2, 12.0 Hz, 1
H), 4.69 (dd, J = 13.4, 3.7 Hz, 1 H), 4.31 (dd, J = 11.9, 3.7 Hz, 1
H), 3.36 (dq, J = 13.3, 7.4 Hz, 1 H), 3.27–3.11 (m, 1 H), 2.08 (hept,
J = 6.8 Hz, 1 H), 1.46 (t, J = 7.4 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 3
H), 0.93 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 209.8 (s), 163.4 (s), 147.9 (s), 136.5 (s), 135.1 (s), 129.4 (s), 124.8
(s), 123.4 (s), 92.4 (s), 75.1 (s), 47.7 (s), 34.3 (s), 25.6 (s), 17.0 (s),
(CDCl ): ν = 2972, 1717, 1558, 1488, 1377, 1073, 974, 908, 737,
˜
3
650 cm–1. HRMS (ESI): calcd. for [C16H19BrN2O3S2 + H]+
431.0093; found 431.0084. HPLC (Chiralpak OD-H column, n-
hexane/iPrOH 90:10, flow rate 1.0 mLmin–1, retention time: tmajor
= 6.5, tminor = 8.1, 94% ee).
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-2-nitro-1-o-tolylethyl]thiazol-
5(4H)-one: Compound 3j was isolated by column chromatography
on silica gel as a single diastereoisomer in 65% yield (23.9 mg, dia-
stereomeric ratio 7:1). White solid; m.p. 87–88 °C. [α]2D0 = +27.38
16.1 (s), 14.6 (s) ppm. IR (CDCl ): ν = 2973, 1717, 1559, 1462,
˜
3
1350, 1095, 975, 736, 692 cm–1. HRMS (ESI): calcd. for
[C16H19N3O5S2 + H]+ 398.0839; found 398.0835. HPLC (Chiralpak
OD-H column, n-hexane/iPrOH 90:10, flow rate 1.0 mLmin–1, re-
tention time: tmajor = 9.4, tminor = 11.7, 93% ee).
1
(c = 0.84 in CHCl3). H NMR (300 MHz, CDCl3): δ = 7.31–7.22
(m, 2 H), 7.15–7.04 (m, 3 H), 5.05 (dd, J = 13.3, 11.7 Hz, 1 H),
4.81 (dd, J = 13.3, 3.7 Hz, 1 H), 4.69 (dd, J = 11.7, 3.7 Hz, 1 H),
3.15 (dq, J = 13.2, 7.4 Hz, 1 H), 2.95 (dq, J = 13.2, 7.4 Hz, 1 H),
2.42 (s, 3 H), 2.27 (hept, J = 6.6 Hz, 1 H), 1.34–1.27 (m, 6 H), 0.85
(d, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 212.4
(s), 161.2 (s), 138.2 (s), 132.9 (s), 130.6 (s), 128.0 (s), 126.1 (s), 126.0
(s), 93.6 (s), 75.2 (s), 42.4 (s), 34.6 (s), 25.0 (s), 20.1 (s), 17.5 (s),
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-2-nitro-1-(4-nitrophenyl)ethyl]-
thiazol-5(4H)-one: Compound 3n was isolated by column
chromatography on silica gel as a single diastereoisomer in 73%
yield (29.0 mg, diastereomeric ratio 5:1). White solid; m.p. 91–92
°C. [α]2D0 = +22.7 (c = 2.11 in CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 8.17 (d, J = 8.9 Hz, 2 H), 7.62–7.48 (m, 2 H), 4.94
(dd, J = 13.4, 11.9 Hz, 1 H), 4.70 (dd, J = 13.4, 3.7 Hz, 1 H), 4.32
(dd, J = 11.9, 3.7 Hz, 1 H), 3.28 (dq, J = 13.3, 7.4 Hz, 1 H), 3.14
(dq, J = 13.2, 7.4 Hz, 1 H), 2.11 (dt, J = 6.6 Hz, 1 H), 1.43 (t, J =
7.4 Hz, 3 H), 1.12 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.0 (s), 163.3 (s), 147.8
(s), 141.8 (s), 130.3 (s), 123.4 (s), 92.5 (s), 74.9 (s), 47.9 (s), 34.4 (s),
17.1 (s), 14.5 (s) ppm. IR (CDCl ): ν = 2967, 1708, 1553, 1441,
˜
3
1377, 1266, 969, 738 cm–1. HRMS (ESI): calcd. for [C17H22N2O3S2
+ H]+ 367.1145; found 367.1149. HPLC (Chiralpak OD-H column,
n-hexane/iPrOH 90:10, flow rate 1.0 mL min–1, retention time:
tminor = 6.1, tmajor = 7.2, 90% ee).
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-2-nitro-1-p-tolylethyl]thiazol-
5(4H)-one: Compound 3k was isolated by column chromatography
on silica gel as a single diastereoisomer in 83% yield (30.5 mg, dia-
stereomeric ratio 8:1). White solid; m.p. 101–102 °C. [α]2D0 = +12.8
25.5 (s), 17.1 (s), 16.3 (s), 14.6 (s) ppm. IR (CDCl ): ν = 2973, 1716,
˜
3
1559, 1348, 974, 861, 699 cm–1. HRMS (ESI): calcd. for
[C16H19N3O5S2 + H]+ 398.0839; found 398.0836. HPLC (Chiralpak
OD-H column, n-hexane/iPrOH 90:10, flow rate 1.0 mLmin–1, re-
tention time: tmajor = 12.4, tminor = 17.5, 92% ee).
1
(c = 1.88 in CHCl3). H NMR (300 MHz, CDCl3): δ = 7.30–7.18
(m, 3 H), 7.08 (d, J = 7.9 Hz, 2 H), 4.86 (dd, J = 12.7, 11.9 Hz, 1
H), 4.61 (dd, J = 12.8, 3.8 Hz, 1 H), 4.13 (dd, J = 11.8, 3.8 Hz, 1
H), 3.35–3.05 (m, 2 H), 2.31 (s, 3 H), 2.12 (hept, J = 6.6 Hz, 1 H),
1.42 (t, J = 7.4 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3 H), 0.91 (d, J =
6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.6 (s), 161.9
(s), 138.0 (s), 131.0 (s), 129.2 (s), 129.0 (s), 93.0 (s), 75.8 (s), 48.1
(s), 34.2 (s), 25.3 (s), 21.1 (s), 17.0 (s), 16.2 (s), 14.7 (s) ppm. IR
(CDCl ): ν = 2971, 1720, 1458, 1558, 1377, 973 cm–1. HRMS (ESI):
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-1-(3-methoxyphenyl)-2-nitroeth-
yl]thiazol-5(4H)-one: Compound 3o was isolated by column
chromatography on silica gel as a single diastereoisomer in 64%
yield (24.5 mg, diastereomeric ratio 9:1). White solid; m.p. 52–53
°C. [α]2D0 = +7.7 (c = 1.16 in CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.20 (t, J = 8.2 Hz, 1 H), 6.97–6.89 (m, 2 H), 6.82 (ddd, J =
8.3, 2.5, 0.9 Hz, 1 H), 4.86 (dd, J = 12.9, 11.7 Hz, 1 H), 4.61 (dd,
J = 12.9, 3.7 Hz, 1 H), 4.15 (dd, J = 11.7, 3.7 Hz, 1 H), 3.78 (s, 3
H), 3.36–3.07 (m, 2 H), 2.15 (hept, J = 6.7 Hz, 1 H), 1.42 (t, J =
7.4 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.5 (s), 162.1 (s), 159.3
(s), 135.8 (s), 129.3 (s), 121.7 (s), 115.3 (s), 113.7 (s), 92.9 (s), 75.8
(s), 55.1 (s), 48.4 (s), 34.3 (s), 25.4 (s), 17.1 (s), 16.3 (s), 14.7 (s) ppm.
˜
3
calcd. for [C17H22N2O3S2 + H]+ 367.1145; found 367.1150. HPLC
(Chiralpak OD-H column, n-hexane/iPrOH 90:10, flow rate
1.0 mLmin–1, retention time: tmajor = 5.1, tminor = 5.7, 92% ee).
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-2-nitro-1-(2-nitrophenyl)ethyl]-
thiazol-5(4H)-one: Compound 3l was isolated by column
chromatography on silica gel as a single diastereoisomer in 84%
yield (33.4 mg, diastereomeric ratio 10:1), or in 76% yield (30.2 mg,
diastereomeric ratio 9:1) when 1 mol-% 4d was used. White solid;
m.p. 99–100 °C. [α]2D0 = –161.4 (c = 1.4 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.84 (dd, J = 8.0, 1.0 Hz, 1 H), 7.62–7.37
(m, 3 H), 5.60 (dd, J = 11.6, 3.9 Hz, 1 H), 5.26 (dd, J = 13.4,
11.7 Hz, 1 H), 4.97 (dd, J = 13.5, 3.9 Hz, 1 H), 3.33 (dq, J = 13.4,
7.4 Hz, 1 H), 2.90 (dq, J = 13.3, 7.4 Hz, 1 H), 2.25 (hept, J =
6.7 Hz, 1 H), 1.38–1.26 (m, 6 H), 0.82 (d, J = 6.6 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 211.7 (s), 163.1 (s), 151.1 (s),
132.6 (s), 129.1 (s), 128.6 (s), 128.0 (s), 125.2 (s), 93.3 (s), 73.3 (s),
40.0 (s), 34.5 (s), 25.1 (s), 17.4 (s), 17.2 (s), 14.1 (s) ppm. IR
IR (CDCl ): ν = 2970, 1718, 1558, 1461, 1378, 1262, 1047, 974,
˜
3
701 cm–1. HRMS (ESI): calcd. for [C17H22N2O4S2 + H]+ 383.1094;
found 383.1089. HPLC (Chiralpak AS-H column, n-hexane/iPrOH
90:10, flow rate 1.0 mLmin–1, retention time: tmajor = 8.8, tminor
15.5, 96% ee).
=
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-1-(4-methoxyphenyl)-2-nitroeth-
yl]thiazol-5(4H)-one: Compound 3p was isolated by column
chromatography on silica gel as a single diastereoisomer in 75%
yield (28.7 mg, diastereomeric ratio 8:1), or in 71% yield (27.2 mg,
6652
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6647–6655

Asymmetric Organocatalytic Michael Addition
diastereomeric ratio 9:1) when 1 mol-% 4d was used. White solid;
m.p. 62–63 °C. [α]2D0 = +10.5 (c = 1.53 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.25 (dd, J = 8.6, 3.1 Hz, 1 H), 6.81 (d, J
= 8.9 Hz, 1 H), 4.93–4.80 (m, 1 H), 4.60 (dd, J = 12.8, 3.8 Hz, 1
H), 4.12 (dd, J = 11.9, 3.8 Hz, 1 H), 3.78 (s, 1 H), 3.36–3.07 (m, 1
H), 2.11 (hept, J = 6.6 Hz, 1 H), 1.43 (t, J = 7.4 Hz, 1 H), 1.08 (d, J
= 6.9 Hz, 1 H), 0.91 (d, J = 6.7 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 210.7 (s), 161.9 (s), 159.3 (s), 130.4 (s), 125.9 (s), 113.7
(s), 93.1 (s), 75.8 (s), 55.1 (s), 47.7 (s), 34.2 (s), 25.3 (s), 17.0 (s),
90:10, flow rate 1.0 mLmin–1, retention time: tminor = 6.6, tmajor
7.2, 96% ee).
=
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-1-(naphthalen-1-yl)-2-nitroeth-
yl]thiazol-5(4H)-one: Compound 3t was isolated by column
chromatography on silica gel as a single diastereoisomer in 64%
yield (25.8 mg, diastereomeric ratio 3:1), or in 60% yield (24.2 mg,
diastereomeric ratio 3:1) when 1 mol-% 4d was used. White solid;
m.p. 75–76 °C. [α]2D0 = –34.4 (c = 1.57 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 8.22 (d, J = 8.6 Hz, 1 H), 7.84–7.73 (m, 2
H), 7.58 (dt, J = 3.0, 1.4 Hz, 1 H), 7.56–7.50 (m, 1 H), 7.46 (ddd,
J = 7.9, 6.9, 1.1 Hz, 1 H), 7.42–7.34 (m, 1 H), 5.37 (dd, J = 11.4,
3.8 Hz, 1 H), 5.22 (dd, J = 13.0, 11.4 Hz, 1 H), 4.95 (dd, J = 13.1,
3.7 Hz, 1 H), 2.81 (dq, J = 13.2, 7.4 Hz, 1 H), 2.50 (dq, J = 13.2,
7.4 Hz, 1 H), 2.32 (hept, J = 6.7 Hz, 1 H), 1.37 (d, J = 6.8 Hz, 3
H), 1.04 (t, J = 7.4 Hz, 3 H), 0.84 (d, J = 6.6 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 212.3 (s), 161.3 (s), 133.8 (s), 132.8
(s), 130.7 (s), 129.0 (s), 128.7 (s), 126.1 (s), 125.5 (s), 124.8 (s), 124.8
(s), 123.7 (s), 93.8 (s), 75.4 (s), 41.0 (s), 34.6 (s), 24.8 (s), 17.6 (s),
16.2 (s), 14.7 (s) ppm. IR (CDCl ): ν = 2970, 1720, 1558, 1513,
˜
3
1461, 1378, 1252, 1181, 1035, 973 cm–1. HRMS (ESI): calcd. for
[C17H22N2O4S2 + H]+ 383.1094; found 383.1088. HPLC (Chiralpak
OD-H column, n-hexane/iPrOH 90:10, flow rate 1.0 mLmin–1, re-
tention time: tmajor = 6.3, tminor = 6.9, 91% ee).
4-{(S)-1-[(S)-2-(Ethylthio)-4-isopropyl-5-oxo-4,5-dihydrothiazol-4-
yl]-2-nitroethyl}benzonitrile: Compound 3q was isolated by column
chromatography on silica gel as a single diastereoisomer in 71%
yield (26.8 mg, diastereomeric ratio 7:1). Colorless oil. [α]2D0 = +31
1
17.1 (s), 14.1 (s) ppm. IR (CDCl ): ν = 2970, 1715, 1558, 1460,
˜
(c = 1.29 in CHCl3). H NMR (300 MHz, CDCl3): δ = 7.60 (d, J
3
1377, 972, 777 cm–1. HRMS (ESI): calcd. for [C20H22N2O3S2
+
= 8.5 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 2 H), 4.92 (dd, J = 13.3,
11.9 Hz, 1 H), 4.68 (dd, J = 13.4, 3.7 Hz, 1 H), 4.25 (dd, J = 11.9,
3.7 Hz, 1 H), 3.37–3.02 (m, 2 H), 2.10 (hept, J = 6.6 Hz, 1 H), 1.42
(t, J = 7.4 Hz, 3 H), 1.12 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.1 (s), 163.2 (s),
139.8 (s), 132.0 (s), 130.1 (s), 118.2 (s), 112.4 (s), 92.5 (s), 74.8 (s),
48.1 (s), 34.4 (s), 25.4 (s), 17.1 (s), 16.3 (s), 14.6 (s) ppm. IR
H]+ 403.1145; found 403.1135. HPLC (Chiralpak OD-H column,
n-hexane/iPrOH 90:10, flow rate 1.0 mL min–1, retention time:
tmajor = 7.2, tminor = 8.3, 92% ee).
(S)-2-(Ethylthio)-4-isopropyl-4-[(S)-1-(naphthalen-2-yl)-2-nitroeth-
yl]thiazol-5(4H)-one: Compound 3u was isolated by column
chromatography on silica gel as a single diastereoisomer in 82%
yield (33.0 mg, diastereomeric ratio 6:1). White solid; m.p. 110–111
(CDCl ): ν = 2972, 2231, 1717, 1558, 1457, 1377, 974, 863 cm–1.
˜
3
HRMS (ESI): calcd. for [C17H19N3O3S2 + H]+ 378.0941; found
°C. [α]2D0 = –9.7 (c = 3.1 in CHCl3). H NMR (300 MHz, CDCl3):
1
378.0943. HPLC (Chiralpak OD-H column, n-hexane/iPrOH
δ = 7.79 (dd, J = 11.4, 6.4 Hz, 4 H), 7.55–7.41 (m, 3 H), 5.10–4.93
(m, 1 H), 4.70 (dd, J = 13.0, 3.7 Hz, 1 H), 4.36 (dd, J = 11.7,
3.7 Hz, 1 H), 3.35–3.10 (m, 2 H), 2.25–2.07 (m, 1 H), 1.43 (t, J =
7.4 Hz, 3 H), 1.09 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.6 (s), 162.2 (s), 133.0
(s), 132.9 (s), 131.7 (s), 128.9 (s), 128.0 (s), 128.0 (s), 127.6 (s), 126.7
(s), 126.4 (s), 126.3 (s), 93.0 (s), 75.8 (s), 48.5 (s), 34.4 (s), 25.4 (s),
90:10, flow rate 1.0 mLmin–1, retention time: tmajor = 12.3, tminor
16.9, 94% ee).
=
(S)-4-[(S)-1-(3,4-Dimethylphenyl)-2-nitroethyl]-2-(ethylthio)-4-iso-
propylthiazol-5(4H)-one: Compound 3r was isolated by column
chromatography on silica gel as a single diastereoisomer in 83%
yield (31.6 mg, diastereomeric ratio 9:1). White solid; m.p. 99–100
17.1 (s), 16.2 (s), 14.7 (s) ppm. IR (CDCl ): ν = 2971, 1718, 1558,
1
˜
°C. [α]2D0 = +4.7 (c = 1.9 in CHCl3). H NMR (300 MHz, CDCl3):
3
1461, 1377, 1267, 973, 818, 749 cm–1. HRMS (ESI): calcd. for
[C20H22N2O3S2 + H]+ 403.1145; found 403.1152. HPLC (Chiralpak
OD-H column, n-hexane/iPrOH 80:20, flow rate 1.0 mLmin–1, re-
tention time: tminor = 7.2, tmajor = 10.5, 83% ee).
δ = 7.26 (s, 1 H), 7.11–6.98 (m, 3 H), 4.86 (dd, J = 12.8, 11.8 Hz,
1 H), 4.60 (dd, J = 12.8, 3.7 Hz, 1 H), 4.10 (dd, J = 11.7, 3.7 Hz,
1 H), 3.33–3.09 (m, 2 H), 2.21 (s, 6 H), 2.18–2.06 (m, 1 H), 1.43 (t,
J = 7.4 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.7 (s), 161.7 (s), 136.6
(s), 136.3 (s), 131.4 (s), 130.9 (s), 129.5 (s), 126.4 (s), 93.0 (s), 75.8
(s), 48.0 (s), 34.2 (s), 25.3 (s), 19.8 (s), 19.4 (s), 17.0 (s), 16.3 (s),
(S)-2-(Ethylthio)-4-[(S)-1-(furan-2-yl)-2-nitroethyl]-4-isopropylthi-
azol-5(4H)-one: Compound 3v was isolated by column chromatog-
raphy on silica gel. The two diastereoisomers were obtained in a
yield of 93 % (31.9 mg, diastereomeric ratio 4:1). Colorless oil.
14.8 (s) ppm. IR (CDCl ): ν = 2971, 1720, 1558, 1454, 1377,
˜
3
973 cm–1. HRMS (ESI): calcd. for [C18H24N2O3S2 + H]+ 381.1301;
found 381.1309. HPLC (Chiralpak OD-H column, n-hexane/iP-
rOH 90:10, flow rate 1.0 mLmin–1, retention time: tminor = 7.3,
tmajor = 8.0, 92% ee).
1
[α]2D0 = –5.24 (c = 2.67 in CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.32 (ddd, J = 2.4, 1.8, 0.9 Hz, 1 H), 6.29 (dd, J = 3.3, 1.9 Hz,
1 H), 6.21 (d, J = 3.1 Hz, 1 H), 4.98 (dd, J = 13.2, 11.7 Hz, 1 H),
4.67 (dd, J = 13.2, 3.5 Hz, 1 H), 4.33 (dd, J = 11.7, 3.5 Hz, 1 H),
3.29–3.07 (m, 2 H), 2.17 (dq, J = 13.4, 6.7 Hz, 1 H), 1.41 (t, J =
7.3 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.2 (s), 162.5 (s), 148.2
(s), 142.7 (s), 110.5 (s), 109.9 (s), 92.1 (s), 73.5 (s), 42.2 (s), 34.1 (s),
(S)-4-[(S)-1-(2,5-Dimethoxyphenyl)-2-nitroethyl]-2-(ethylthio)-4-iso-
propylthiazol-5(4H)-one: Compound 3s was isolated by column
chromatography on silica gel as a single diastereoisomer in 71%
yield (29.3 mg, diastereomeric ratio 9:1). Yellow oil. [α]2D0 = –45.9
25.4 (s), 17.1 (s), 16.6 (s), 14.6 (s) ppm. IR (CDCl ): ν = 2972, 1722,
˜
3
1
(c = 2.42 in CHCl3). H NMR (300 MHz, CDCl3): δ = 7.24 (d, J
1560, 1462, 1377, 1267, 1149, 974, 742 cm–1. HRMS (ESI): calcd.
for [C14H18N2O4S2 + H]+ 343.0781; found 343.0774. HPLC (Chi-
ralpak OD-H column, n-hexane/iPrOH 98:2, flow rate
= 13.0 Hz, 1 H), 6.80 (dd, J = 7.2, 3.2 Hz, 2 H), 5.08–4.75 (m, 1
H), 4.75–4.34 (m, 2 H), 3.75 (s, 6 H), 3.15 (s, 2 H), 2.18 (d, J =
6.6 Hz, 1 H), 1.38 (s, 3 H), 1.12–0.92 (m, 3 H), 0.90 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 209.9 (s), 161.4 (s),
153.2 (s), 152.0 (s), 124.5 (s), 113.9 (s), 112.1 (s), 55.5 (s), 34.7 (s),
1.0 mLmin–1, retention time: t1major = 7.2, t1minor = 9.6, t2major
7.5, t2minor = 8.7, 88%/83% ee).
=
29.7 (s), 25.2 (s), 17.2 (s), 15.6 (s), 14.7 (s) ppm. IR (CDCl ): ν = (S)-2-(Ethylthio)-4-isopropyl-4-[(S)-2-nitro-1-(thiophen-2-yl)ethyl]-
˜
3
2969, 1722, 1558, 1501, 1462, 1378, 1224, 1050, 973, 808, 744 cm–1. thiazol-5(4H)-one: Compound 3w was isolated by column
HRMS (ESI): calcd. for [C18H24N2O5S2 + H]+ 413.1199; found
413.1189. HPLC (Chiralpak OD-H column, n-hexane/iPrOH
chromatography on silica gel as a single diastereoisomer in 80%
yield (28.7 mg, diastereomeric ratio 5:1). White solid; m.p. 40–41
Eur. J. Org. Chem. 2012, 6647–6655
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6653

X. Liu, H. Song, Q. Chen, W. Li, W. Yin, M. Kai, R. Wang
+ H]+ 392.1097; found 392.1086. HPLC (Chiralpak OD-H column,
FULL PAPER
°C. [α]2D0 = –19.6 (c = 1.8 in CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.28 (dd, J = 5.2, 0.8 Hz, 1 H), 7.01 (dd, J = 3.5, 1.0 Hz, 1 H), n-hexane/iPrOH 90:10, flow rate 1.0 mL min–1, retention time:
6.93 (dd, J = 5.1, 3.5 Hz, 1 H), 4.67 (dd, J = 12.3, 11.4 Hz, 1 H),
4.60–4.44 (m, 2 H), 3.38 (dq, J = 13.3, 7.4 Hz, 1 H), 3.23 (dq, J =
13.3, 7.4 Hz, 1 H), 2.19 (hept, J = 6.9 Hz, 1 H), 1.48 (t, J = 7.4 Hz,
3 H), 1.00 (dd, J = 6.8, 2.2 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 209.3 (s), 163.0 (s), 136.4 (s), 128.5 (s), 126.6 (s), 126.4
(s), 92.5 (s), 44.3 (s), 34.4 (s), 25.7 (s), 16.7 (s), 15.8 (s), 14.7 (s) ppm.
tmajor = 12.9, tminor = 10.7, 84% ee).
4-{(S)-1-[(S)-2-(Benzylthio)-4-isopropyl-5-oxo-4,5-dihydrothiazol-4-
yl]-2-nitroethyl}benzonitrile: Compound 3zЈ was isolated by column
chromatography on silica gel as a single diastereoisomer in 71%
yield (31.2 mg, diastereomeric ratio 4:1). White solid; m.p. 133–134
°C. [α]2D0 = +51.3 (c = 1.91 in CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.47 (d, J = 8.5 Hz, 2 H), 7.44–7.36 (m, 4 H), 7.36–
7.28 (m, 1 H), 7.22 (d, J = 8.3 Hz, 2 H), 4.79 (dd, J = 13.3, 11.9 Hz,
1 H), 4.60 (dd, J = 13.4, 3.8 Hz, 1 H), 4.47–4.31 (m, 2 H), 4.15
(dd, J = 11.9, 3.7 Hz, 1 H), 2.03 (dd, J = 13.5, 6.8 Hz, 1 H), 1.06
(d, J = 6.8 Hz, 3 H), 0.83 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 209.7 (s), 162.4 (s), 139.5 (s), 135.9 (s), 131.9
(s), 130.1 (s), 128.7 (s), 128.7 (s), 127.9 (s), 118.3 (s), 112.3 (s), 92.6
(s), 74.5 (s), 48.0 (s), 35.0 (s), 34.2 (s), 17.0 (s), 16.2 (s) ppm. IR
IR (CDCl ): ν = 2972, 1720, 1559, 1436, 1377, 973, 705 cm–1
.
˜
3
HRMS (ESI): calcd. for [C14H18N2O3S3 + H]+ 359.0552; found
359.0543. HPLC (Chiralpak OD-H column, n-hexane/iPrOH
90:10, flow rate 1.0 mLmin–1, retention time: tmajor = 6.4, tminor
8.5, 87% ee).
=
(S)-2-(Ethylthio)-4-isopropyl-4-[(S,E)-1-nitro-4-phenylbut-3-en-2-yl]-
thiazol-5(4H)-one: Compound 3x was isolated by column
chromatography on silica gel. The two diastereoisomers were ob-
tained in a yield of 66% (25.0 mg, diastereomeric ratio 1:4). White
(CDCl ): ν = 2972, 2230, 1720, 1558, 1454, 1377, 977, 703 cm–1.
˜
3
HRMS (ESI): calcd. for [C22H21N3O3S2 + H]+ 440.1097; found
1
solid; m.p. 30–31 °C. [α]2D0 = –30.3 (c = 2.01 in CHCl3). H NMR
440.1090. HPLC (Chiralpak OD-H column, n-hexane/iPrOH
(300 MHz, CDCl3): δ = 7.36–7.29 (m, 4 H), 7.29–7.24 (m, 1 H),
6.56 (d, J = 15.8 Hz, 1 H), 6.13–5.99 (m, 1 H), 4.55–4.37 (m, 2 H),
3.81 3.67 (m, 1 H), 3.38–3.11 (m, 2 H), 2.33–2.17 (m, 1 H), 1.44
(dt, J = 10.0, 7.4 Hz, 3 H), 1.06 (dd, J = 6.8, 3.1 Hz, 3 H), 0.99 (t,
J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, main): δ =
209.7 (s), 162.2 (s), 136.7 (s), 136.0 (s), 128.5 (s), 128.2 (s), 126.6
(s), 122.2 (s), 92.4 (s), 75.5 (s), 47.0 (s), 34.2 (s), 25.4 (s), 16.9 (s),
90:10, flow rate 1.0 mLmin–1, retention time: tminor = 36.8, tmajor
41.1, 92% ee).
=
Transformation of Adduct 3 Into Compounds 5 and 6: Concd. aque-
ous HCl (0.2 mL) was added at 0 °C to a stirred solution of com-
pound 3 (0.1 mmol) and SnCl2 (0.8 mmol) in EtOH (1 mL). The
reaction was stirred for 4 h at room temperature and monitored by
TLC. After the reaction was complete, the mixture was concen-
trated under reduced pressure and diluted with CH2Cl2 (2 mL).
The mixture was then made basic to pH 9 with ammonia and
quenched with CH2Cl2 (2ϫ5 mL). The combined organic extracts
were dried with Na2SO4 and purified by flash silica chromatog-
raphy (DCM/MeOH 40:1, Rf = 0.4) to afford 5.
15.8 (s), 14.7 (s) ppm. IR (CDCl ): ν = 2972, 1721, 1558, 1450,
˜
3
1378, 1333, 972, 749 cm–1. HRMS (ESI): calcd. for [C18H22N2O3S2
+ H]+ 379.1145; found 379.1149. HPLC (Chiralpak OD-H column,
n-hexane/iPrOH 90:10, flow rate 1.0 mL min–1, retention time:
t1major = 6.0, t1minor = 22.4, t2minor = 6.5, t2major = 7.0, 97%/70% ee).
(S)-2-(Ethylthio)-4-isobutyl-4-[(S)-2-nitro-1-(2-nitrophenyl)ethyl]thi-
azol-5(4H)-one: Compound 3y was isolated by column chromatog-
raphy on silica gel as a single diastereoisomer in 62 % yield
(25.5 mg, diastereomeric ratio 3:1). White solid; m.p. 97–98 °C.
(Boc)2O (0.12 mmol) was added at room temperature to a stirred
solution of the major diastereoisomer of compound 5 (0.1 mmol)
and EtN3 (0.15 mmol) in THF (2 mL). The mixture was then
stirred for 6 h at the same temperature. The reaction mixture was
concentrated under reduced pressure and purified by silica gel col-
umn chromatography (petroleum ether/ethyl acetate 9:1) to afford
6 (91% yield).
1
[α]2D0 = –47.1 (c = 1.55 in CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.85 (dd, J = 8.1, 1.3 Hz, 1 H), 7.67 (dd, J = 7.9, 1.4 Hz, 1 H),
7.59 (td, J = 7.7, 1.3 Hz, 1 H), 7.52–7.42 (m, 1 H), 5.14 (dd, J =
10.8, 4.4 Hz, 1 H), 4.89 (dd, J = 13.7, 10.8 Hz, 1 H), 4.78 (dd, J =
13.7, 4.5 Hz, 1 H), 3.28 (dq, J = 13.2, 7.4 Hz, 1 H), 3.12 (dq, J =
13.1, 7.4 Hz, 1 H), 1.88 (dd, J = 13.9, 6.5 Hz, 1 H), 1.76 (dd, J =
13.9, 5.5 Hz, 1 H), 1.69–1.52 (m, 1 H), 1.38 (t, J = 7.4 Hz, 3 H),
0.85 (dd, J = 6.6, 2.3 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 210.1 (s), 162.7 (s), 151.3 (s), 132.7 (s), 129.2 (s), 129.2 (s), 128.7
(s), 125.0 (s), 90.1 (s), 74.9 (s), 45.7 (s), 43.5 (s), 25.2 (s), 24.4 (s),
(S)-4-[(S)-2-Amino-1-(4-methoxyphenyl)ethyl]-2-(ethylthio)-4-iso-
propylthiazol-5(4H)-one: Compound 5a was isolated by column
chromatography on silica gel as a single diastereoisomer in 78%
yield (28.8 mg, diastereomeric ratio 9:1). Colorless oil. [α]2D0 = +6.6
1
(c = 0.75 in CHCl3). H NMR (300 MHz, CDCl3): δ = 7.24 (d, J
= 8.3 Hz, 2 H), 6.94 (s, 1 H), 6.76 (d, J = 8.3 Hz, 2 H), 4.01 (d, J
= 13.5 Hz, 1 H), 3.83 (dd, J = 13.4, 5.2 Hz, 2 H), 3.75 (s, 3 H),
3.24 (s, 1 H), 3.13–2.87 (m, 2 H), 1.20–1.03 (m, 9 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 196.7 (s), 158.6 (s), 130.4 (s), 128.9
(s), 114.1 (s), 113.4 (s), 77.4 (s), 77.0 (s), 76.6 (s), 70.2 (s), 56.4 (s),
55.2 (s), 44.7 (s), 34.5 (s), 30.0 (s), 18.3 (s), 16.9 (s), 13.9 (s) ppm.
24.2 (s), 24.0 (s), 14.3 (s) ppm. IR (CDCl ): ν = 2962, 1720, 1558,
˜
3
1446, 1355, 971, 735 cm–1. HRMS (ESI): calcd. for [C17H21N3O5S2
+ H]+ 412.0995; found 412.1005. HPLC (Chiralpak OD-H column,
n-hexane/iPrOH 90:10, flow rate 1.0 mL min–1, retention time:
tminor = 7.5, tmajor = 10.2, 80% ee).
IR (CDCl ): ν = 3300, 2966, 1698, 1513, 1362, 1247, 1181, 1031,
˜
3
4-{(S)-1-[(R)-4-tert-Butyl-2-(ethylthio)-5-oxo-4,5-dihydrothiazol-4-
yl]-2-nitroethyl}benzonitrile: Compound 3z was isolated by column
chromatography on silica gel as a single diastereoisomer in 68%
833 cm–1. HRMS (ESI): calcd. for [C17H24N2O2S2 + NH4]+
370.1617; found 370.1629.
yield (26.7 mg, diastereomeric ratio 9:1). Colorless oil. [α]2D0 = –30.2
(S)-4-[(S)-2-Amino-1-(3-aminophenyl)ethyl]-2-(ethylthio)-4-isoprop-
(c = 2.15 in CHCl3). H NMR (300 MHz, CDCl3): δ = 7.62 (d, J ylthiazol-5(4H)-one: Compound 5b was isolated by column
1
= 8.3 Hz, 2 H), 7.46 (d, J = 8.3 Hz, 2 H), 5.41 (dd, J = 13.8, 4.4 Hz,
1 H), 4.89 (dd, J = 13.8, 10.1 Hz, 1 H), 4.46 (dd, J = 10.1, 4.4 Hz,
1 H), 2.61 (dq, J = 11.7, 7.5 Hz, 1 H), 2.42 (dq, J = 11.7, 7.4 Hz,
1 H), 1.25 (t, J = 7.5 Hz, 3 H), 1.15 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 190.7 (s), 174.5 (s), 138.7 (s), 131.9 (s), 130.4
(s), 118.0 (s), 113.0 (s), 91.6 (s), 75.9 (s), 52.9 (s), 36.0 (s), 27.3 (s),
chromatography on silica gel as a single diastereoisomer in 82%
yield (29.1 mg, diastereomeric ratio 10:1). Colorless oil. [α]2D0
=
1
–78.0 (c = 0.5 in CHCl3). H NMR (300 MHz, CDCl3): δ = 7.02
(t, J = 7.8 Hz, 2 H), 6.69 (d, J = 7.7 Hz, 2 H), 6.60–6.48 (m, 1 H),
5.59 (s, 2 H), 3.99 (t, J = 7.7 Hz, 1 H), 3.91–3.71 (m, 2 H), 3.21 (s,
1 H), 3.13–2.90 (m, 2 H), 1.12 (m, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 196.8 (s), 166.1 (s), 145.8 (s), 139.7 (s), 128.9 (s), 119.8
24.2 (s), 13.6 (s) ppm. IR (CDCl ): ν = 2971, 2231, 1705, 1558,
˜
3
1438, 1373, 867, 735 cm–1. HRMS (ESI): calcd. for [C18H21N3O3S2 (s), 116.3 (s), 114.2 (s), 77.4 (s), 77.0 (s), 76.6 (s), 70.1 (s), 55.9 (s),
6654
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Eur. J. Org. Chem. 2012, 6647–6655

Asymmetric Organocatalytic Michael Addition
Burgess, Bioorg. Med. Chem. Lett. 2004, 14, 1619; g) H.-J.
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45.2 (s), 34.5 (s), 30.0 (s), 18.3 (s), 17.0 (s), 14.0 (s) ppm. IR
(CDCl ): ν = 3310, 2926, 1698, 1612, 1498, 1364, 1015, 911,
˜
3
732 cm–1. HRMS (ESI): [C16H23N3OS2 + NH4]+ calcd. for
355.1621; found 355.1642.
tert-Butyl (S)-2-[(S)-2-(Ethylthio)-4-isopropyl-5-oxo-4,5-dihydrothi-
azol-4-yl]-2-(4-methoxyphenyl)ethylcarbamate: Compound 6a was
isolated by column chromatography on silica gel as a single dia-
stereoisomer in 91% yield (42.7 mg, diastereomeric ratio Ͼ99:1).
Colorless oil. [α]2D0 = –1.1 (c = 1.8 in CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.35–7.24 (m, 2 H), 6.86 (s, 1 H), 6.79 (t, J = 5.9 Hz,
2 H), 3.98 (dt, J = 12.1, 7.6 Hz, 2 H), 3.83 (d, J = 5.4 Hz, 1 H),
3.77 (s, 3 H), 3.20 (s, 1 H), 3.01 (q, J = 7.3 Hz, 2 H), 1.56 (s, 9 H),
1.20–1.06 (m, 9 H), 0.91–0.81 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 196.9 (s), 166.5 (s), 158.7 (s), 150.8 (s), 130.4 (s), 113.4
(s), 86.2 (s), 77.4 (s), 77.0 (s), 76.6 (s), 68.7 (s), 55.2 (s), 54.6 (s),
44.4 (s), 34.5 (s), 30.0 (s), 27.5 (s), 18.2 (s), 16.9 (s), 14.0 (s) ppm.
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IR (CDCl ): ν = 3291, 2974, 1789, 1732, 1514, 1368, 1251, 1151,
˜
3
1026, 834, 733 cm–1. HRMS (ESI): calcd. for [C22H32N2O4S2
+
NH4]+ 470.2142; found 470.2127. HPLC (Chiralpak OD-H col-
umn, n-hexane/iPrOH 95:5, flow rate 1.0 mLmin–1, retention time:
tmajor = 9.6, tminor = 14.0, 93% ee).
Supporting Information (see footnote on the first page of this arti-
cle): Detailed biological studies, copies of spectra of all products
and X-ray information of compound 3i.
Acknowledgments
We are grateful for grants from the National Natural Science Foun-
dation of China (NSFC) (grant numbers 20932003 and 90813012)
and the Key National S & T Major Project and Major New Drugs
Development of China (grant number 2012ZX09504-001-003).
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data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/daa_request/cif.
Received: August 13, 2012
Published Online: October 9, 2012
Eur. J. Org. Chem. 2012, 6647–6655
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6655