Organocatalytic enantioselective transient enolate protonation in conjugate addition of thioacetic acid to a-substituted n-acryloyloxazolidinones

Article abstract of DOI:10.1016/j.tetlet.2013.01.004

Organocatalytic conjugate addition of thioacetic acid to a series of a-substituted N-acryloyloxazolidin-2- ones followed by enantioselective protonation has been studied in the presence of thiourea catalysts derived from cinchona alkaloids. Conjugate addition/protonation adducts have been obtained up to 97% ee and high yields. The methodology could serve as an easy and practical route to the syntheses of useful biologically active molecules.

Full text of DOI:10.1016/j.tetlet.2013.01.004

Tetrahedron Letters 54 (2013) 1911–1915
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic enantioselective transient enolate protonation in conjugate
addition of thioacetic acid to a-substituted N-acryloyloxazolidinones
Rajshekhar A. Unhale a, Nirmal K. Rana b, Vinod K. Singh a,b,
⇑
a Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal 460 023, India
b Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Organocatalytic conjugate addition of thioacetic acid to a series of a-substituted N-acryloyloxazolidin-2-
Received 31 October 2012
Revised 31 December 2012
Accepted 3 January 2013
Available online 10 January 2013
ones followed by enantioselective protonation has been studied in the presence of thiourea catalysts
derived from cinchona alkaloids. Conjugate addition/protonation adducts have been obtained up to
97% ee and high yields. The methodology could serve as an easy and practical route to the syntheses
of useful biologically active molecules.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Thiourea
Sulfa-Michael
Thioacetic acid
a-Substituted N-acryloyloxazolidinones
Optically active molecules having tertiary carbon stereocenter
addition has gained a lot of interest for the construction of carbon–
sulfur bond due to the availability of diversity of electrophilic and
nucleophilic partners. Much of these studies have been directed to
asymmetric sulfa-Michael addition of different sulfur centered
nucleophiles to b-substituted activated olefins.7 Despite consider-
able advance in this field, the scope of sulfa-Michael addition to
are extremely common structural motif in valuable biologically ac-
tive natural products and pharmaceutical agents.1 Enantioselective
protonation of a prostereogenic enolate derivative has been shown
to be a convenient and practical method for the preparation of
enantiomerically enriched carbonyl compounds having a tertiary
asymmetric carbon at the
a
-position.2 The importance of such
a
-substituted acrylates followed by enantioselective protonation
reactions is reasonably narrow.8 Specifically, the catalytic conju-
gate addition of thioacids to a range of -substituted Michael
building blocks in biology and organic synthesis makes it a worth-
while goal to achieve. Several strategies have emerged for enantio-
selective protonation by exploiting various means of
enantiocontrol through different mechanisms. The earlier methods
were based on the protonation of lithium enolates in the presence
of an excess of chiral proton source.3 Recent approaches involve
the catalytic protonation of pre-formed enolates.4 An attractive
alternative is the generation of a transient enolate involving conju-
a
acceptors has not been utilized yet. Although, quite efficient enan-
tioselective protonation in conjugate addition of thioacids to meth-
acryloyl substrate with chiral auxiliary is reported, the substrate
scope for this reaction is relatively low.9
The catalytic conjugate addition of thioacids to
a-substituted
acrylates is highly desirable because the resulting thioesters could
easily be hydrolyzed in mild conditions to give synthetically and
therapeutically useful compounds having free mercapto group.
Therefore, further advances toward the development of organocat-
alytic processes capable of promoting high level of asymmetric
induction with substrate generality remain to be accomplished.
Cinchona alkaloid derived thiourea catalysts, in particular, have
been found very efficient for several enantioselective transforma-
tions.10 In our previous report on asymmetric protonation in sul-
fa-Michael addition of thiols, we have found that quinine derived
thiourea 1a was an efficient bifunctional catalyst for the reaction
gated addition reaction of a nucleophile to an
a-substituted a,b-
unsaturated carbonyl compound followed by an in situ enantiose-
lective protonation of the resulting transient enolate which enables
the installation of different functional groups at the b-position.5 In
particular, such molecules containing sulfur functional group are
integral part of many drug molecules and important intermediates
for the syntheses of physiologically active natural products.6
Therefore, a great deal of recent interest has been focused to pre-
pare and manipulate chiral organosulfur species with chirality
residing at sulfur, at carbon, or at both. Asymmetric sulfa-Michael
(Scheme 1).11 Also
a-substituted N-acryloyloxazolidinone was
found to be an excellent acyclic template for asymmetric proton-
ation in conjugate addition of thiols11 and malonates.5i We have
envisioned that the replacement of thiol with thioacid as a
⇑
Corresponding author. Fax: +91 512 2597436.
E-mail address: vinodks@iitk.ac.in (V.K. Singh).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.004

1912
R. A. Unhale et al. / Tetrahedron Letters 54 (2013) 1911–1915
1a (1 mol %),
We were delighted to observe that the enantioselectivity of the
O
O
O
O
toluene, rt
reaction increased to a greater extent when the catalyst loading
was decreased from 10 to 0.5 mol % (Table 1, entry 8). However,
further lowering of the catalyst loading to 0.1 mol % causes a slight
decrease in enantioselectivity. It has been found that 1.5 equiv of
thioacetic acid was optimum in terms of both yield and enantiose-
lectivity (Table 1, entry 11). Subsequently, the influence of the sol-
vent on the stereochemical outcome of the reaction was examined.
Less polar solvents proved to be more effective. Among several less
polar solvents screened, toluene was found to be the best and the
product was obtained in 84% ee (Table 2, entry 16).
After initial optimization of the reaction conditions with cata-
lyst 1a, various cinchona alkaloid derived (thio) urea catalysts
(Fig. 1) were employed in the above reaction, and the results are
summarized in Table 3. Intensive screening of catalysts disclosed
the significant impact of the substituent and catalyst’s chiral scaf-
fold on the enantioselectivity. Thiourea catalysts were found to be
more efficient over corresponding urea derivatives having same
chiral environment (Table 3, entries 1–4). Very low enantioselec-
tivity with epi-quinine derived catalyst 1e emphasizes the impor-
tance of the correct relative orientation of thiourea and
quinuclidine functional groups in the catalyst’s chiral scaffold (Ta-
ble 3, entry 5). It is interesting to note that the antipode of 3a was
obtained up to 87% ee when pseudoenantiomeric catalysts 1f–g
were used, as per our expectation (Table 3, entries 6 and 7). To
our delight, catalyst 1h derived from cinchonidine afforded prod-
ucts with 90% ee (Table 3, entries 8 and 10). However, when 60-cin-
chona thiourea 1i was used for the reaction, poor enantioselectivity
was observed (Table 3, entry 9). Replacing thioacetic acid with
thiobenzoic acid as a nucleophile, it was noticed that the corre-
sponding addition/protonation product 3aa was afforded only in
moderate enantioselectivity (Table 3, entry 11).
RSH
N
O
RS
N
O
Previous Work11
R1
R1 = aryl, alkyl
R1
yield = up to 99%
ee = up to 96%
R = aryl, hetero-aryl, alkyl
bifunctional
O
O
O
O
organocatalyst
AcSH
N
O
AcS
N
O
This Work
R1
R1
Scheme 1. Asymmetric protonation in conjugate addition of sulfa-Michael addition
to -substituted acrylate derivatives.
a
nucleophile would work in a similar fashion in the conjugate addi-
tion to -substituted acrylate derivatives in the catalytic influence
a
of cinchona alkaloid derived thiourea (Scheme 1) and, if successful,
would be an excellent and easy route to the synthesis of biologi-
cally active captopril and cysteine derivatives. Very few catalytic
literature reports for the preparation of such valuable scaffold with
high enantiopurity are available to date.12 Here, we wish to dem-
onstrate a catalytic enantioselective transient enolate protonation
in the conjugate addition of thioacetic acid to
acryloyloxazolidinones with bifunctional organocatalyst derived
a-substituted N-
from cinchona alkaloid.
Initial attempts were made to test our hypothesis by carrying
out the conjugate addition of thioacetic acid to N-methacry-
loyloxazolidinone, an excellent template for asymmetric proton-
ation found previously, in the catalytic influence of quinine
derived thiourea 1a (10 mol %). We were pleased to find that the
product was obtained in excellent yield and impressive enantiose-
lectivity (Table 1, entry 1). Lowering the reaction temperature to
0 °C led to an increase in enantioselectivity to some extent (Table 1,
entry 2). However, further lowering of temperature resulted in
lower chemical yield and enantioselectivity of the reaction (Table 1,
entries 3 and 4). Thus, to improve the asymmetric induction, fur-
ther optimization studies were conducted by keeping the reaction
temperature constant at 0 °C.
In search for a suitable prochiral template, several methacryloyl
derivatives 2b–d were tested under the optimized conditions and
Table 2
Solvent screeninga
O
O
O
O
1a (0.5 mol %),
Solvent, 0 °C
AcSH
N
O
AcS
N
O
Table 1
Optimization of reaction conditionsa
2a
3a
O
O
O
O
Entry
Solvent
Time (d)
Yield (%)
eeb (%)
1a, toluene
AcSH
N
O
AcS
N
O
1
2
3
4
5
6
7
8
9
10
11
12
13c
14c
15c
16d
17e
18f
19g
Toluene
m-Xylene
o-Xylene
Mesitylene
n-Hexane
CH3CN
DMF
THF
Et2O
CH2Cl2
CHCl3
DCE
1,4-Dioxane
p-Xylene
Benzene
Toluene
Toluene
Toluene
Toluene
3
3
3
3
3
3
3
3
3
3
3
3
1
1
1
3
3
3
3
90
96
92
95
72
66
96
65
95
79
85
78
74
98
85
86
73
91
95
82
77
71
74
37
27
0
53
65
51
53
67
9
78
75
84
82
79
71
2a
3a
Entry
1a Mol %
Temp (°C)
Time (d)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
10
10
10
5
rt
0
ꢀ5
ꢀ20
0
0
0
0
0
0
0
0
0
1
2
2
2
3
3
3
3
3
3
3
3
3
3
98
98
90
75
98
95
90
82
80
77
90
96
99
99
59
67
63
51
72
77
78
80
77
77
82
78
75
69
2
1
0.5
0.1
0.5
0.5
0.5
0.5
0.5
10c
11d
12e
13f
14g
0
a
a
All reactions were carried out on 0.2 mmol of 2a and 0.24 mmol of thioacetic
All reactions were carried out on 0.2 mmol of 2a and 0.3 mmol of thioacetic acid
acid in 1 mL toluene, unless noted otherwise.
in 1 mL solvent, unless noted otherwise.
b
b
Determined by HPLC using chiral column.
0.2 mmol of thioacetic acid.
0.3 mmol of thioacetic acid.
0.4 mmol of thioacetic acid.
Determined by HPLC using Chiralpak IA3 column.
At room temperature.
In 1.5 mL toluene.
In 2 mL toluene.
c
c
d
d
e
e
f
f
0.6 mmol of thioacetic acid.
In 0.5 mL toluene.
g
g
0.8 mmol of thioacetic acid.
In 250 lL toluene.

R. A. Unhale et al. / Tetrahedron Letters 54 (2013) 1911–1915
1913
R
R
X
F3C
CF3
F3C
F3C
HN
HN
HN
HN
S
N
H
H
H
N
NH
S
N
H
N
R'
MeO
MeO
N
N
N
1a:
1b:
R = CF3, X = S
1e
1f:
R' = OMe
R' = H
F3C
CF3
R = H, X= S
1g:
1c: R = CF3, X = O
1d:
R = H, X = O
F3C
S
CF3
HN
HN
S
Ph
H
H
O
NH
N
N
HN
N
N
1h
1i
Figure 1. Cinchona alkaloid derived (thio) urea catalysts.
Table 3
estingly, 2-(o-methoxyphenyl) acryloyloxazolidin-2-one 2m fur-
nished the corresponding product in 97% ee (Table 4, entry 10).
Screening of different chiral catalysts and prochiral templatesa
O
O
However, a-substituted N-acryloyloxazolidinones having naphthyl
1 (0.5 mol %),
toluene, 0 °C, 3 d
group had a considerable impact on the enantioselectivities. The
addition/protonation adducts containing 2-naphthyl derivatives
were formed in moderate ees (Table 4, entries 14 and 16). On the
other hand, 1-naphthyl substituted Michael acceptor afforded
product with excellent enantioselectivity (97% ee, Table 4, entry
15). It is important to note that, due to their crystalline nature, a
few of the products were recrystallized from dichloromethane
and hexane to achieve up to 99.9% ee (Table 4, entries 4, 7–10,
and 14)
AcSH
Z
AcS
Z
2
3
O
O
O
O
Z =
N
O
N
N
N
N
N
2a
2b
Ph 2c
2d
Ph
Entry
Catalyst
2
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
1h
1h
1h
1h
1h
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
86
74
79
75
78
75
73
84
78
92
98
88
80
99
84
77
67
46
7
77
87
90
11
90
53
69
14
50
Finally, the synthetic potential of the protonated adduct was
studied. The adduct 3a-(S) was readily converted into (S)-3-mer-
capto-2-methylpropanoic acid 4 in high yield without the loss of
optical purity. It could be transformed to orally active angioten-
sin-converting enzyme inhibitor captopril, which is widely pre-
Table 4
Substrate scope of conjugate addition followed by enantioselective protonationa
10c
11d
12c
13c
14c
O
O
O
O
1h (0.5 mol %),
toluene, 0 °C, 4 d
AcSH
N
O
AcS
N
O
R1
R1
3a, 3e-s
2a, 2e-s
a
All reactions were carried out on 0.2 mmol of 2 and 0.3 mmol of thioacetic acid
in 1.5 mL of toluene, unless noted otherwise.
Entry
R1
3
Yield (%)
eeb (%)
b
Determined by HPLC using chiral column.
4 days.
c
1
2
Me (2a)
3a
3e
3f
3g
3h
3i
92
82
98
90
90
90
nBu (2e)
PhCH2 (2f)
Ph (2g)
d
Thiobenzoic acid as nucleophile.
3
4c
5
98 (47)
99
86 (99)
85
4-F-C6H4 (2h)
4-Cl-C6H4 (2i)
6
95
84
it was found that N-methacryloyloxazolidinone eventually came
out as an efficient template (Table 3, entries 12–14).
7
8
9
10
11
12
13
14
15
16
4-Me-C6H4 (2j)
3-Me-C6H4 (2k)
4-MeO-C6H4 (2l)
2-MeO-C6H4 (2m)
4-nBu-C6H4 (2n)
4-tBu-C6H4 (2o)
4-iBu-C6H4 (2p)
2-Naphthyl (2q)
1-Naphthyl (2r)
3j
3k
3l
3m
3n
3o
3p
3q
3r
98 (50)
99 (56)
97 (56)
99 (76)
93
92
96
95 (25)
98
86 (98)
90 (99)
86 (97)
97 (99.9)
85
85
90
75 (97)
97
Having identified the optimized reaction conditions, a series of
a-substituted N-acryloyloxazolidinones were investigated in the
conjugate addition with thioacetic acid. Most of the substrates
underwent the reaction smoothly and the corresponding products
were obtained in excellent yields and enantioselectivities (Table 4).
The aliphatic substituted templates as Michael acceptors furnished
excellent enantioselectivities in general (Table 4, entries 1–3). We
were delighted to observe that the products with aryl substitution
were also obtained in high to excellent enantiopurity with high
yields (Table 4, entries 4–13). The electronic nature of the substitu-
tion at the aromatic ring of the Michael acceptors had no effect as
such on yield and enantioselectivities (Table 4, entries 4–13). Inter-
2-(6-MeO-naphthyl) (2s)
3s
94
75
a
All reactions were carried out on 0.2 mmol of 2 and 0.3 mmol of thioacetic acid
in 1.5 mL of toluene, unless noted otherwise.
Determined by HPLC using chiral column and data in the parenthesis were
obtained after recrystallization.
Absolute configuration of 3g was determined to be (R) by single crystal X-ray
analysis.
b
c

1914
R. A. Unhale et al. / Tetrahedron Letters 54 (2013) 1911–1915
O
thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi for a S. P. Mukharjee fellowship. N.K.R. thanks the CSIR
for a senior research fellowship (SRF). We thank Dr. Vishnumaya
Bisai (IISER Bhopal), Atanu Dey, and Sumit K. Ray (IIT Kanpur) for
their help.
O
O
O
2 N HCl,
ref. 9d
120 °C, 6 h
HS
N
AcS
N
O
HS
OH
80% yield
HO2C
4
3a-(S)
87% ee
87% ee
Captopril
Supplementary data
O
1h (0.5 mol %), AcSH,
O
N
O
O
toluene, 0 °C, 6 d
N
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.004.
*
O
O
90% yield
O
AcS
O
71% ee
5
6
Scheme 2. Applications of the addition/protonation products.
References and notes
1. (a)The Total Synthesis of Natural Products; ApSimon, J., Ed.; John Wiley & Sons:
Ottawa, 1992; Vol. 9, (b) Jamali, F.; Mehvar, R.; Russell, A. S.; Sattari, S.;
Yakimets, W. W.; Koo, J. J. Pharm. Sci. 1992, 81, 221; (c) Harrison, I. T.; Lewis, B.;
Nelson, P.; Rooks, W.; Roszkowoski, A.; Tomolonis, A.; Fried, J. H. J. Med. Chem.
1970, 13, 203.
2. (a) Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2004,
15, 3653; (b) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009, 1, 359.
3. For selected examples, see: (a) Duhamel, L.; Plaquevent, J.-C. J. Am. Chem. Soc.
1978, 100, 7415; (b) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J.
Am. Chem. Soc. 1996, 118, 12854; (c) Yanagisawa, A.; Watanabe, T.; Kikuchi, T.;
Yamamoto, H. J. Org. Chem. 2000, 65, 2979.
N
N
CF3
CF3
S
N
S
N
H
H
N
F3C
N
H
N
H
O
N
H
N
H
O
F3C
N
H
H
O
O
SAc
SAc
O
O
R1
R1
4. For recent examples, see: (a) Vedejs, E.; Kruger, A. W.; Lee, N.; Sakata, S. T.; Stec,
M.; Suna, E. J. Am. Chem. Soc. 2000, 122, 4602; (b) Wang, W.; Xu, M.-H.; Lei, X.-
S.; Lin, G.-Q. Org. Lett. 2000, 2, 3773; (c) Reynolds, N. T.; Rovis, T. J. Am. Chem.
Soc. 2005, 127, 16406; (d) Poisson, T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer,
S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090; (e) Cheon, C. H.;
Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246; (f) Poisson, T.; Gembus, V.;
Dalla, V.; Oudeyer, S.; Levacher, V. J. Org. Chem. 2010, 75, 7704; (g) Cheon, C. H.;
Imahori, T.; Yamamoto, H. Chem. Commun. 2010, 46, 6980; (h) Uraguchi, D.;
Kinoshita, N.; Ooi, T. J. Am. Chem. Soc. 2010, 132, 12240.
5. (a) Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.; Sacramento, J. J. Chem. Soc.,
Perkin Trans. 1 2001, 3167; (b) Belokon, Y. N.; Harutyunyan, S.; Vorontsov, E. V.;
Peregudov, A. S.; Chrustalev, V. N.; Kochetkov, K. A.; Pripadchev, D.; Sagyan, A.
S.; Beck, A. K.; Seebach, D. ARKIVOC 2004, 132; (c) Hamashima, Y.; Somei, H.;
Shimura, Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004, 6, 1861; (d) Navarre, L.;
Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719; (e) Sibi, M. P.;
Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571; (f) Frost, C. G.; Penrose, S. D.;
Lambshead, K.; Raithby, P. R.; Warren, J. E.; Gleave, R. Org. Lett. 2007, 9, 2119;
(g) Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130,
6159; (h) Morita, M.; Drouin, L.; Motoki, R.; Kimura, Y.; Fujimori, I.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3858; (i) Poisson, T.; Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2010, 132, 7890; (j) Duan, S.-W.; An, J.; Chen, J.-
R.; Xiao, W.-J. Org. Lett. 2011, 13, 2290.
7
Delivery of proton to the top face
N
(Si face) of the enolate
H
H
N
O
H
O
S
N
H
H
SAc
R1
H
N
SAc
O
O
F3C
N
R1
N
O
O
7
CF3
Figure 2. Possible transition state model.
scribed for the treatment of hypertension (Scheme 2).9d Reaction
between 2-phthalimidoacrylate derivative 5 and thioacetic acid
under optimized conditions yielded the corresponding product 6
in good enantiomeric excess (71% ee) enabling a direct access to
enantioenriched cysteine derivative (Scheme 2).
A plausible transition state model to explain the high stereo-
chemical outcome of the reaction is shown in Figure 2. We believe
that the bifunctional catalyst simultaneously activates thioacetic
acid through acid–base interaction and Michael acceptor 2 via dou-
ble H-bondings. Initial conjugate addition of nucleophile to 2 gen-
erates a transient ion pair 7. Subsequent delivery of the proton
from the quinuclidine nitrogen to the top face (Si face) of the gen-
erated prochiral enolate leads to the formation of the major stereo-
isomer (Fig. 2).
6. (a) Ondetti, M. A.; Rubin, B.; Cushman, D. W. Science 1977, 196, 411; (b)
Cushman, D. W.; Cheung, H. S.; Sabo, E. F.; Ondetti, M. A. Biochemistry 1977, 16,
5484; (c) Park, J. D.; Kim, D. H. J. Med. Chem. 2002, 45, 911.
7. For review see: (a) Enders, D.; Lüttgen, K.; Narine, A. A. Synthesis 2007, 959; (b)
Clayden, J.; MacLellan, P. Beilstein J. Org. Chem. 2011, 7, 582; For recent
examples see: (c) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128,
10354; (d) Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am. Chem. Soc.
2007, 129, 1036; (e) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.;
Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49; (f) Lu, H.-H.; Zhang, F.-G.; Meng,
X.-G.; Duan, S.-W.; Xiao, W.-J. Org. Lett. 2009, 11, 3946; (g) Liu, Y.; Sun, B.;
Wang, B.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418; (h) Kimmel, K.
L.; Robak, M. T.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 8754; (i) Dai, L.; Wang,
S.-X.; Chen, F.-E. Adv. Synth. Catal. 2010, 352, 2137; (j) Hui, Y.; Jiang, J.; Wang,
W.; Chen, W.; Cai, Y.; Lin, L.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2010, 49,
4290; (k) Rana, N. K.; Selvakumar, S.; Singh, V. K. J. Org. Chem. 2010, 75, 2089;
(l) Ingle, G. K.; Mormino, M. G.; Wojtas, L.; Antilla, J. C. Org. Lett. 2011, 13, 4822;
(m) Bonollo, S.; Lanari, D.; Pizzo, F.; Vaccaro, L. Org. Lett. 2011, 13, 2150; (n)
Tian, X.; Cassani, C.; Liu, Y.; Moran, A.; Urakawa, A.; Galzerano, P.; Arceo, E.;
Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 17934; (o) Zhao, F.; Zhang, W.; Yang,
Y.; Pan, Y.; Chen, W.; Liu, H.; Yan, L.; Tan, C.-H.; Jiang, Z. Adv. Synth. Catal. 2011,
353, 2624; (p) Dai, L.; Yang, H.; Chen, F. Eur. J. Org. Chem. 2011, 5071; (q) Ueno,
M.; Kitanosono, T.; Sakai, M.; Kobayashi, S. Org. Biomol. Chem. 2011, 9, 3619; (r)
Rana, N. K.; Unhale, R.; Singh, V. K. Tetrahedron Lett. 2012, 53, 2121; (s) Palacio,
C.; Connon, S. J. Chem. Commun. 2012, 48, 2849; For diastereoselectiove sulfa-
Michael addition see: (t) Wang, J.; Xie, H.; Li, H.; Zu, L.; Wang, W. Angew. Chem.,
Int. Ed. 2008, 47, 4177; Tandem thio-amination reaction, see: (u) Galzerano, P.;
Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009,
48, 7892.
In conclusion, we have developed an effective catalytic conju-
gate addition of thioacetic acid to a range of a-substituted N-acry-
loyloxazolidin-2-ones 2 followed by enantioselective protonation
using thiourea catalyst 1h derived from cinchona alkaloid. This ap-
proach offers several advantages such as operational simplicity,
low catalyst loading (0.5 mol %), and the products were obtained
in high to excellent enantioselectivities (up to 97% ee) with almost
quantitative yields. It is noteworthy that both enantiomers of addi-
tion/protonation products could be obtained with the same level of
enantioselectivities. The synthetic utility of the present catalytic
asymmetric protonation reaction was established by transforming
the products to useful intermediates of biological importance.
8. (a) Tsai, W.-J.; Lin, Y.-T.; Uang, B.-J. Tetrahedron: Asymmetry 1994, 5, 1195; (b)
Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043; (c)
Henze, R.; Duhamel, L.; Lasne, M.-C. Tetrahedron: Asymmetry 1997, 8, 3363; (d)
Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. Angew. Chem., Int. Ed. 2001, 40,
440; (e) Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y. J. Chem. Soc., Chem.
Commun. 1991, 485; (f) Dai, L.; Yang, H.; Niu, J.; Chen, F.-E. Synlett 2012, 314;
Acknowledgments
V.K.S. thanks the Department of Science and Technology (DST),
India for a research grant through J. C. Bose fellowship. R.A.U.

R. A. Unhale et al. / Tetrahedron Letters 54 (2013) 1911–1915
1915
(g) Kitanosono, T.; Sakai, M.; Ueno, M.; Kobayashi, S. Org. Biomol. Chem. 2012,
10, 7134.
10. (a)Cinchona Alkaloids in Synthesis and Catalysis; Song, C. E., Ed.; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, 2009; (b) Connon, S. J. Chem. Commun.
2008, 2499; (c) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229; (d) Yeboah, E.
M. O.; Yeboah, S. O.; Singh, G. S. Tetrahedron 2011, 67, 1725.
11. Rana, N. K.; Singh, V. K. Org. Lett. 2011, 13, 6520.
12. (a) Pracejus, H.; Wilcke, F.-W.; Hanemann, K. J. Prakt. Chem. 1977, 319, 219; (b)
Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008,
47, 5641.
9. (a) Effenberger, F.; Isak, H. Chem. Ber. 1989, 122, 553; (b) Tseng, T.-C.; Wu, M.-J.
Tetrahedron: Asymmetry 1995, 6, 1633; (c) Kim, B. H.; Lee, H. B.; Hwang, J. K.;
Kim, Y. G. Tetrahedron: Asymmetry 2005, 16, 1215; (d) Shimazaki, M.;
Hasegawa, J.; Kan, K.; Nomura, K.; Nose, Y.; Kondo, H.; Ohashi, T.; Watanabe,
K. Chem. Pharm. Bull. 1982, 30, 3139.