Quinine-catalyzed enantioselective desymmetrization of meso-aziridines with benzenethiols

Article abstract of DOI:10.1016/j.tetasy.2008.03.017

Ring opening of meso-aziridines with benzenethiols utilizing quinine as an organocatalyst has been developed. The reaction proceeded smoothly in the presence of 10 mol % of quinine in CHCl₃ to afford β-amino sulfides in high yields and with mod

Full text of DOI:10.1016/j.tetasy.2008.03.017

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 964–969
Quinine-catalyzed enantioselective desymmetrization
of meso-aziridines with benzenethiols
Zhiyong Wang, Xiaoyu Sun, Shengqing Ye, Weizi Wang, Bing Wang* and Jie Wu*
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
Received 25 February 2008; accepted 19 March 2008
Abstract—Ring opening of meso-aziridines with benzenethiols utilizing quinine as an organocatalyst has been developed. The reaction
proceeded smoothly in the presence of 10 mol % of quinine in CHCl3 to afford b-amino sulfides in high yields and with moderate to good
enantioselectivities.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
salts as the catalyst, which gave rise to the corresponding
chiral b-amino sulfides in moderate to good enantioselec-
tivities (40–73% ee). Subsequently, the enantioselective
ring-opening of meso-aziridines with azide nucleophiles
was described in the presence of a catalytic amount of a
chiral phosphoric acid catalyst.7b The products were gener-
ated in excellent yield and enantioselectivity. Herein, we re-
port another example using an organocatalyst for the
desymmetrization of meso-aziridines.
Aziridines represent one of the most valuable three
membered ring systems in modern synthetic chemistry be-
cause of its widely recognized versatility as a significant
building block for chemical bond elaborations and func-
tional group transformations. Its powerful synthetic utility
has been extensively demonstrated in the literature for azi-
ridine preparation, and its broad applications to other syn-
theses.1–5 Compared to the desymmetrization of meso-
epoxides, there are less examples for the desymmetrization
of meso-aziridines with nucleophiles, which is considered as
a formidable challenge due to both the low reactivity of
aziridines and the general difficulty in the differentiation
of enantiotopic centers.6,7 The biggest problem, in general,
is that the efficiencies of the catalysts have been found to be
substrate-dependent, since varied reaction conditions were
needed for various aziridines and nucleophiles because of
the different reactivity of the substrates and reagents, as
well as the complexity of the structure of aziridines.
Although several examples using a chiral Lewis acid cata-
lyst have appeared in the literature,6 most of them suffered
from high catalyst loading, substrate scope limitation, pro-
longed reaction times, excess amount of reagents, and the
need for expensive and/or heavy metal salts to be
employed. Recently, Hou7a reported that desymmetriza-
tion of meso-N-sulfonylaziridines with thiols was realized
using cinchonine-derived chiral quaternary ammonium
The interest in this field of organocatalysis has increased
greatly over the last few years.8 A tertiary amine as an
organocatalyst is an example of a ‘privileged catalyst’ class.
It is able to mediate a wide variety of transformations.9 For
instance, DABCO (1,4-diaza-bicyclo[2.2.2]octane) and its
analogues show high efficiency in Morita–Baylis–Hillman
reactions9b as well as the cyanation of ketones.10 Recently,
we also found that it was efficient as a catalyst in the ring-
opening reactions of aziridines11 or epoxides12 with various
nucleophiles, such as amines or thiols. In this reaction pro-
cess, tertiary amines act as nucleophilic triggers.11 We con-
ceive that enantiomeric products may be generated if the
chiral tertiary amine could be employed in the desymmetric
reactions of meso-azidirines with nucleophiles. Thus, we
started to investigate the possibility of desymmetrization
of meso-aziridines with nucleophiles, such as thiols. To
the best of our knowledge, only two such examples have
been reported in the literature. Oguni6b,c reported that chi-
ral zinc complexes [prepared from diethylzinc and dialkyl
L-(+)-tartrate] could promote the asymmetric ring opening
reactions of N-acylaziridines with thiols. However, a large
excess amount of zinc complexes was necessary in the
*
Corresponding authors. Fax: +86 216 510 2412 (J.W.); e-mail:
jie_wu@fudan.edu.cn
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.017

Z. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 964–969
965
reaction. Another example was presented by Hou7a as
2. Results and discussion
described above. On the other hand, Deng and other
authors9 discovered that natural cinchona alkaloids may
be utilizing both the tertiary amine and the hydroxyl group
to activate and orientate both the nucleophile and electro-
phile, respectively, thus achieving optimum asymmetric
catalysis. Prompted by these results and our efforts for
aziridine transformations,13 we hypothesized that a natural
cinchona alkaloid such as quinine, upon interaction with
both a nucleophile (chiral Lewis-base catalysis) and an
electrophile (nucleophilic catalysis) through the suitable
atoms of the catalyst, might also be able to form a rigid
pocket around the activated nucleophile or electrophile,
thereby allowing them to function as efficient chiral
Lewis-base or nucleophilic organic catalysts.
To verify the hypothesis, a set of experiments were carried
out using N-tosylaziridine 1a with benzenethiol 2a as mod-
el substrates. This preliminary survey, carried out in the
presence of quinine as the catalyst at 25 °C, allowed us to
evaluate and optimize the catalytic system. In an initial
experiment, the desired b-amino sulfide 3a could be affor-
ded in 51% ee with 36% yield when the reaction was per-
formed in the presence of quinine (10 mol %) using
toluene as the solvent (Table 1, entry 1). Changing the
amount of quinine catalyst did not improve the result.
For instance, 40% ee of product 3a was obtained when
5 mol % of quinine was employed in the reaction (Table
1, entry 2). When the amount of quinine did increase to
Table 1. Condition screening for desymmetrization of N-tosylaziridine 1a with benzenethiol 2a
Cat.
NHTs
SPh
SH
(10 mol %)
NTs
+
solvent, r.t.
1a
2a
3a
Cat.
H3C
H3C
CH3
O
CH3
N
H
N
H
N
H
N
H
N N
O
O
O
O
O
O
H
H
H
H
O
O
O
N
N
N
N
(DHQ)2PHAL
(DHQ)2AQN
H
OMe
OMe
N
OH
OBn
N
H
HO
N
N
H
N
H
Cinchonidine
Quinine
Catalyst
9-BnO-Quinine
Solvent
N
Entry
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Quinine (10 mol %)
Quinine (5 mol %)
Toluene
Toluene
Toluene
EtOH
CH2Cl2
CHCl3
CCl4
THF
MeCN
Et2O
n-Hexane
(CH2Cl)2
Xylene
CHCl3
CHCl3
CHCl3
CHCl3
36
35
78
99
55
85
57
34
86
31
98
35
49
39
57
13
73
51
40
49
5
42
72
34
3
Quinine (100 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
Quinine (10 mol %)
(DHQ)2PHAL (10 mol %)
(DHQ)2AQN (10 mol %)
9-BnO-Quinine (10 mol %)
Cinchonidine (10 mol %)
5
17
42
46
49
4
3
41
45
a Isolated yield based on aziridine 1a.
b Ee value was determined by chiral HPLC.

966
Z. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 964–969
Table 2. Desymmetrization of N-tosylaziridine 1a with benzenethiol 2
catalyzed by quinine (10 mol %) in CHCl3 at room temperature
100 mol %, similar enantioselectivity was observed,
although the yield did increase to 78% (Table 1, entry 3).
After preliminary screening of solvents and cinchona alka-
loids, we found that this result could be dramatically
improved upon when the reaction took place in CHCl3
(Table 1, entry 4; 72% ee, 85% yield). The absolute config-
uration of the ring opening product 3a was assigned as
(S,S) via comparison with a previous report.7a Inferior
results were displayed when other solvents were utilized
in the reaction. For example, moderate enantioselectivities
(42–49% ee) were obtained when several non-polar solvents
(CH2Cl2, CCl4, ClCH2CH2Cl, n-hexane, xylene) were
employed in the reaction (Table 1, entries 5, 7, and
11–13). However, only 5% ee was generated when EtOH
was used in the reaction (Table 1, entry 4). Similar results
were also observed when the solvent was replaced as
THF (3% ee), CH3CN (5% ee), or Et2O (17% ee) (Table
1, entries 8–10). The heteroatom (O or N) in the solvents
may deactivate the hydroxyl group in the quinine via a
hydrogen bond. Further investigation revealed that the
protection of hydroxyl group in quinine retarded the
reaction and decreased the enantioselectivity, which
demonstrated the critical role of the hydroxyl group in
the reaction process (Table 1, entries 14–16). For instance,
only 4% ee with 39% yield was generated when
(DHQ)2PHAL was employed in the reaction as a replace-
ment for the quinine catalyst (Table 1, entry 14). Cincho-
nidine was also used in the reaction and the desired
product 3a was afforded in 45% ee with 73% yield (Table
1, entry 17). Changing the temperature did not improve
the result (data not shown in Table 1). We also synthesized
a series of chiral thiourea catalysts,14 and applied them in
the same reaction as shown in Table 1, however, no better
results were generated.
Quinine
NHTs
S
SH
(10 mol %)
NTs
+
R
R
CHCl3, r.t.
1a
Entry
2
3
Thiol 2
Product 3
Yielda (%)
eeb (%)
72
SH
SH
1
2
3a
85
2a
3b
3c
52
80
50
32
CH3
2b
SH
3
But
But
2c
SH
4
5
3d
3e
53
82
63
56
CH3
2d
SH
Cl
2e
SH
6
3f
71
42
Cl
2f
a Isolated yield based on aziridine 1a.
b Ee value was determined by chiral HPLC.
was generated when N-3,5-dinitrobenzoyl aziridine 1e was
employed (Table 3, entry 4). However, inferior results were
observed when other acyl groups were used; no enantiose-
lectivity was detected when N-Boc aziridine 1i was used
(Table 3, entry 8).
We next investigated the reaction scope of this quinine
catalytic system under the optimized conditions [quinine
(10 mol %), CHCl3, 25 °C] (Tables 2 and 3). For reactions
of N-tosylaziridine 1a with various benzenethiols (Table 2),
the corresponding products were generated in moderate ee.
For example, N-tosylaziridine 1a reacted with 2-methylben-
zenethiol 2b to give the desired product 3b in 52% yield with
50% ee (Table 2, entry 2). When 2-methyl-5-tert-butylbenze-
nethiol 2d was utilized in the reaction the expected product
3d was obtained in 63% ee (Table 2, entry 4). 2-Chlorobenze-
nethiol 2e or 4-chlorobenzenethiol 2f was also employed in
the reaction with N-tosylaziridine 1a, with 56% or 42% ee
being observed, respectively (Table 2, entries 5 and 6).
3. Conclusion
In conclusion, we have described quinine as an efficient
organocatalyst for the enantioselective desymmetrization
of meso-aziridines with benzenethiols, which gives rise to
the b-amino sulfides in high yields and with moderate to
good enantioselectivities. Efforts to explore other nucleo-
philes for desymmetrization of meso-aziridines using chiral
organocatalyst are currently in progress in our laboratory.
In a second set of experiments, the scope of the process
with respect to N-substituted aziridines was investigated
(Table 3). Most of the expected products were generated
in good yields with moderate enantioselectivities under
our standard experimental conditions. Aziridine 1b reacted
with benzenethiol 2a leading to the formation of product
3g in 54% ee with 80% yield (Table 3, entry 1); while
36% ee of product 3h was observed when aziridine 1c
was used as a replacement (Table 3, entry 2). When aziri-
dine 1d was utilized as a substrate in the reaction, the
desired product 3i was afforded in 52% ee (Table 3, entry
3). N-Acylaziridines were also examined in the reaction
of benzenethiol 2a. For instance, 45% ee of product 3j
4. Experimental
All the reactions were performed in test tubes under a
nitrogen atmosphere. Flash column chromatography was
˚
performed using silica gel (60 A pore size, 32–63 lm, stan-
dard grade). Analytical thin–layer chromatography was
performed using glass plates pre-coated with 0.25 mm
230–400 mesh silica gel impregnated with a fluorescent
indicator (254 nm). Solvents were re-distilled prior to use
in the reactions. Aziridines 1a–c,15 1d,16 1e–g,6g 1f,6c

Z. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 964–969
967
Table 3. Desymmetrization of N-substituted aziridine 1 with benzenethiol
2a catalyzed by quinine (10 mol %) in CHCl3 at room temperature
removed and the residue purified on a flash chromatogra-
phy column to afford the desired compound 3.
Quinine
R
R
SH
R
R
NHG
SPh
(10 mol %)
4.2. 4-Methyl-N-((1S,2S)-2-(phenylthio)cyclohexyl)-
benzenesulfonamide 3a11
N G
+
CHCl3, r.t.
1
3
2a
1H NMR (400 MHz, CDCl3) (ppm) 1.25–1.39 (m, 4H),
1.54–1.61 (m, 2H), 2.00–2.03 (m, 1H), 2.28–2.30 (m, 1H),
2.44 (s, 3H), 2.89–2.96 (m, 2H), 5.18 (s, 1H), 7.21–7.17
(m, 5H), 7.30 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz,
2H). HPLC analysis: Daicel Chiralcel OD-H (hexane/
iPrOH = 96/4, 1.0 mL/min, 230 nm), tr-(R,R) 15.38 min,
tr-(S,S) 18.31 min.
Entry
1
Aziridine 1
Product 3
Yielda
(%)
eeb
(%)
NTs
3g
80
54
1b
NTs
2
3
3h
3i
65
72
36
52
1c
4.3. 4-Methyl-N-((1S,2S)-2-(o-tolylthio)cyclohexyl)-
benzenesulfonamide 3b7a
O
NTs
1d
1H NMR (400 MHz, CDCl3) (ppm) 1.23–1.46 (m, 4H),
1.56–1.63 (m, 2H), 1.96–2.00 (m, 1H), 2.24–2.27 (m, 1H),
2.32 (s, 3H), 2.42 (s, 3H), 2.98–3.00 (m, 1H), 3.05–3.08
(m, 1H), 5.19 (s, 1H), 7.16–7.21 (m, 4H), 7.27 (d,
J = 8.1 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H). HPLC analysis:
Daicel Chiralpak AD-H (hexane/iPrOH = 85/15, 1.0 mL/
min, 214 nm), tr-(R,R) 7.36 min, tr-(S,S) 9.62 min.
O
N
4
3j
87
45
NO2
O2N
1e
O
4.4. N-((1S,2S)-2-(4-tert-Butylphenylthio)cyclohexyl)-
4-methylbenzenesulfonamide 3c7a
N
5
6
3k
74
85
42
24
1H NMR (400 MHz, CDCl3) (ppm) 1.23–1.38 (m, 13H),
1.58–1.63 (m, 2H), 1.99–2.03 (m, 1H), 2.30–2.32 (m, 1H),
2.43 (s, 3H), 2.83–2.86 (m, 1H), 2.93–2.95 (m, 1H), 5.34
(s, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.24–7.26 (m, 2H), 7.30
(d, J = 7.8 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H). HPLC anal-
ysis: Daicel Chiralpak AD-H (hexane/iPrOH = 90/10,
1.0 mL/min, 214 nm), tr-(R,R) 8.84 min, tr-(S,S) 14.00 min.
NO2
1f
O
N
3l
CF3
F3C
1g
4.5. N-((1S,2S)-2-(5-tert-Butyl-2-methylphenylthio)-
cyclohexyl)-4-methylbenzenesulfonamide 3d
N
Cbz
7
8
3m
3n
30
45
19
0
1h
1i
1H NMR (400 MHz, CDCl3) (ppm) 1.21–1.38 (m, 13H),
1.57–1.62 (m, 2H), 1.96–1.99 (m, 1H), 2.27–2.30 (m, 1H),
2.33 (s, 3H), 2.42 (s, 3H), 2.91–2.93 (m, 1H), 3.03–3.05
(m, 1H), 5.16 (d, J = 4.6 Hz, 1H), 7.12–7.21 (m, 2H),
7.24–7.26 (m, 2H), 7.37 (d, J = 1.8 Hz, 1H), 7.70 (d,
J = 8.3 Hz, 2H). 13C NMR (400 MHz, CDCl3) (ppm)
20.3, 21.5, 23.2, 24.3, 31.2, 34.3, 46.1, 50.9, 55.6, 124.7,
127.2, 129.5, 130.1, 130.2, 133.1, 137.1, 137.4, 143.2,
149.5. MS (ESI): m/z 432.0 (M++1). Anal. Calcd for
C24H33NO2S2: C, 66.78; H, 7.71, N, 3.24. Found: C,
66.69; H, 7.57, N, 3.42. HPLC analysis: Daicel Chiralpak
AD-H (hexane/iPrOH = 95/5, 1.0 mL/min, 214 nm),
tr-(R,R) 8.27 min, tr-(S,S) 9.68 min.
N
Boc
a Isolated yield based on aziridine 1a.
b Ee value was determined by chiral HPLC.
1h–i6c,17 were prepared according to the literature proce-
dures. Other commercial reagents were used as received.
High-performance liquid chromatography was carried out
using the following apparatus: SHIMADZU LC-20AT (li-
quid chromatograph), SHIMADZU SPD-20A (UV detec-
tor), column, Daicel Chiralpak AD-H, AS-H, or Daicel
Chiralcel OD-H.
4.6. N-((1S,2S)-2-(2-Chlorophenylthio)cyclohexyl)-
4-methylbenzenesulfonamide 3e
4.1. General procedure for desymmetrization of aziridine 1
with benzenethiol 2
1H NMR (400 MHz, CDCl3) (ppm) 1.25–1.61 (m, 6H),
2.00–2.04 (m, 1H), 2.24–2.27 (m, 1H), 2.32 (s, 3H), 2.42
(s, 3H), 3.08 (s, 2H), 5.22 (s, 1H), 7.17–7.21 (m, 2H), 7.27
(d, J = 8.2 Hz, 2H), 7.33–7.40 (m, 2H), 7.74 (d,
J = 8.3 Hz, 2H). 13C NMR (400 MHz, CDCl3) (ppm)
21.6, 23.2, 24.2, 31.3, 32.5, 50.2, 55.3, 127.3, 127.4, 128.4,
To a solution of quinine (3.3 mg, 0.01 mmol) and aziridine
1 (0.1 mmol) in CHCl3 (1.0 mL) was added benzenethiol 2
(0.11 mmol) under a nitrogen atmosphere. The reaction
mixture was stirred at room temperature. After completion
of the reaction as indicated by TLC, the solvent was

968
Z. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 964–969
129.7, 130.1, 133.2, 136.4, 137.1, 143.5. MS (ESI): m/z
396.0 (M++1). Anal. Calcd for C19H22ClNO2S2: C,
57.63; H, 5.60, N, 3.54. Found: C, 57.38; H, 5.57, N,
3.42. HPLC analysis: Daicel Chiralpak AD-H
(hexane/iPrOH = 85/15, 1.0 mL/min, 214 nm), tr-(R,R)
8.50 min, tr-(S,S) 11.13 min.
88/12, 1.0 mL/min, 214 nm), tr-(R,R) 10.85 min, tr-(S,S)
15.82 min.
4.12. 4-Nitro-N-((1S,2S)-2-(phenylthio)cyclohexyl)-
benzamide 3k6c
1H NMR (400 MHz, CDCl3) (ppm) 1.26–1.48 (m, 4H),
1.74–1.81 (m, 2H), 2.16–2.35 (m, 2H), 3.06–3.11 (m, 1H),
3.91–3.94 (m, 1H), 6.22 (s, 1H), 7.26–7.41(m, 5H), 7.75
(d, J = 8.7 Hz, 2H), 8.22 (d, J = 9.1 Hz, 2H). HPLC anal-
ysis: Daicel Chiralpak AD-H (hexane/iPrOH = 85/15,
1.0 mL/min, 214 nm), tr-(R,R) 13.24 min, tr-(S,S) 23.49 min.
4.7. N-((1S,2S)-2-(4-Chlorophenylthio)cyclohexyl)-
4-methylbenzenesulfonamide 3f11
1H NMR (400 MHz, CDCl3) (ppm) 1.25–1.43 (m, 4H),
1.56–1.60 (m, 2H), 1.97–2.01 (m, 1H), 2.19–2.25 (m, 1H),
2.43 (s, 3H), 2.91–3.00 (m, 2H), 5.34 (s, 1H), 7.20–7.26
(m, 4H), 7.28 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 8.2 Hz,
2H). HPLC analysis: Daicel Chiralpak AS-H (hexane/
iPrOH = 50/50, 1.0 mL/min, 214 nm), tr-(R,R) 10.92 min,
tr-(S,S) 25.53 min.
4.13. N-((1S,2S)-2-(Phenylthio)cyclohexyl)-
3,5-bis(trifluoromethyl)benzamide 3l
1H NMR (400 MHz, CDCl3) (ppm) 1.31–1.51 (m, 4H),
1.75–1.81 (m, 2H), 2.19–2.26 (m, 2H), 3.12–3.15 (m, 1H),
3.98–4.01 (m, 1H), 6.35 (d, J = 7.8 Hz, 1H), 7.16–7.25
(m, 3H), 7.39–7.41 (m, 2H), 7.95 (s, 1H), 8.04 (s, 2H).
13C NMR (400 MHz, CDCl3) (ppm) 24.5, 25.9, 33.1,
33.6, 51.7, 54.8, 121.5, 124.2, 124.8, 127.1, 127.4, 129.0,
131.4, 131.7, 132.1, 132.4, 132.6, 133.8, 136.6, 163.9. MS
(ESI): m/z 448.0 (M++1). Anal. Calcd for C21H19F6NOS:
C, 56.37; H, 4.28, N, 3.13. Found: C, 56.48; H, 4.57, N,
3.32. HPLC analysis: Daicel Chiralcel OD-H (hexane/
iPrOH = 95/5, 1.0 mL/min, 214 nm), tr-(R,R) 5.76 min,
tr-(S,S) 10.12 min.
4.8. 4-Methyl-N-((1S,6S)-6-(phenylthio)cyclohex-
3-enyl)benzenesulfonamide 3g7a
1H NMR (400 MHz, CDCl3) (ppm) 1.83–1.87 (m, 1H),
2.13–2.18 (m, 1H), 2.43 (s, 3H), 2.57–2.74 (m, 2H), 3.37–
3.40 (m, 2H), 5.03 (d, J = 5.5 Hz, 1H), 5.53 (d,
J = 10.1 Hz, 1H), 5.63 (d, J = 10.5 Hz, 1H), 7.26–7.28
(m, 7H), 7.68 (d, J = 8.2 Hz, 2H). HPLC analysis: Daicel
Chiralpak AS-H (hexane/iPrOH = 60/40, 1.0 mL/min,
214 nm), tr-(R,R) 13.13 min, tr-(S,S) 35.24 min.
4.9. 4-Methyl-N-((1S,2S)-2-(phenylthio)cyclopentyl)-
benzenesulfonamide 3h7a
4.14. Benzyl (1S,2S)-2-(phenylthio)cyclohexylcarbamate
3m18
1H NMR (400 MHz, CDCl3) (ppm) 1.47–1.60 (m, 4H),
1.65–1.71 (m, 2H), 2.43 (s, 3H), 3.27–3.34 (m, 2H), 4.80
(d, J = 4.2 Hz, 1H), 7.25–7.28 (m, 7H), 7.66 (d,
J = 8.1 Hz, 2H). HPLC analysis: Daicel Chiralcel OD-H
(hexane/iPrOH = 95/5, 1.0 mL/min, 214 nm), tr-(R,R)
17.59 min, tr-(S,S) 20.11 min.
1H NMR (400 MHz, CDCl3) (ppm) 1.20–1.45 (m, 4H),
1.63–1.71 (m, 2H), 2.05–2.21 (m, 2H), 2.88–2.92 (m, 1H),
3.46–3.48 (m, 1H), 4.92, (s, 1H), 5.10 (s, 2H), 7.23–7.25
(m, 3H), 7.31–7.36 (m, 5H), 7.40–7.43 (m, 2H). HPLC
analysis: Daicel Chiralcel OD-H (hexane/iPrOH = 95/5,
1.0 mL/min, 214 nm), tr-(R,R) 10.64 min, tr-(S,S) 16.51 min.
4.10. 4-Methyl-N-((3S,4R)-4-(phenylthio)-tetrahydro-
furan-3-yl)benzenesulfonamide 3i7a
4.15. tert-Butyl (1S,2S)-2-(phenylthio)cyclohexylcarbamate
3n19
1H NMR (400 MHz, CDCl3) (ppm) 2.43 (s, 3H), 3.59–3.70
(m, 4H), 3.97 (dd, J = 9.6, 4.6 Hz, 1H), 4.20–4.25 (m, 1H),
7.26–7.29 (m, 7H), 7.59 (d, J = 8.2 Hz, 2H). HPLC analy-
sis: Daicel Chiralpak AD-H (hexane/iPrOH = 80/20,
1.0 mL/min, 214 nm), tr-(R,R) 11.32 min, tr-(S,S) 33.86 min.
1H NMR (400 MHz, CDCl3) (ppm) 1.20–1.41 (m, 4H),
1.45 (s, 9H), 1.63–1.70 (m, 2H), 2.05–2.19 (m, 2H), 2.84–
2.88 (m, 1H), 3.37–3.40 (m, 1H), 4.66, (s, 1H), 7.21–7.29
(m, 3H), 7.44 (d, J = 7.8 Hz, 2H). HPLC analysis: Daicel
Chiralpak AD-H (hexane/iPrOH = 98/2, 1.0 mL/min,
214 nm), tr-(R,R) 12.77 min, tr-(S,S) 14.20 min.
4.11. 3,5-Dinitro-N-((1S,2S)-2-(phenylthio)cyclohexyl)-
benzamide 3j
1H NMR (400 MHz, CDCl3) (ppm) 1.36–1.52 (m, 4H),
1.79–1.83 (m, 2H), 2.21–2.30 (m, 2H), 3.13–3.16 (m, 1H),
3.99–4.02 (m, 1H), 6.26 (d, J = 7.8 Hz, 1H), 7.20–7.26
(m, 3H), 7.40 (d, J = 7.8 Hz, 2H), 8.75 (d, J = 1.4 Hz,
2H), 9.13 (s, 1H). 13C NMR (400 MHz, CDCl3) (ppm)
24.6, 25.9, 33.0, 33.6, 51.5, 55.1, 120.9, 127.1, 127.3,
129.0, 132.4, 133.7, 137.9, 148.4, 162.0. MS (ESI): m/z
402.0 (M++1). Anal. Calcd for C19H19N3O5S: C, 56.85;
H, 4.77, N, 10.47. Found: C, 56.68; H, 4.57, N, 10.42.
HPLC analysis: Daicel Chiralpak AD-H (hexane/iPrOH =
Acknowledgments
We thank Dr. Renhua Fan for his invaluable advice during
the course of this research. Financial support from the
National Natural Science Foundation of China
(20772018), Shanghai Pujiang Program, and Program for
New Century Excellent Talents in University (NCET-07-
0208) is gratefully acknowledged.

Z. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 964–969
969
M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M.
Tetrahedron 2007, 63, 5820; (j) Arai, K.; Lucarini, S.; Salter,
M. M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2007, 129, 8103.
References
1. Rai, K. M. L.; Hassner, A. Adv. Strain. Interest. Org. Mol.
2000, 8, 187–257.
7. (a) Luo, Z.-B.; Hou, X.-L.; Dai, L.-X. Tetrahedron: Asym-
metry 2007, 18, 443; (b) Rowland, E. B.; Rowland, G. B.;
Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129,
12084.
8. For examples, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 1520; (b) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138.
9. For examples, see: (a) Tian, S.-K.; Chen, Y.; Hang, J.; Tang,
L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621; (b)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
10. Tian, S.-K.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125,
9900.
11. Wu, J.; Sun, X.; Li, Y. Eur. J. Org. Chem. 2005, 4271.
12. Wu, J.; Xia, H.-G. Green Chem. 2005, 7, 708.
13. For selected examples, see: (a) Sun, X.; Sun, W.; Fan, R.; Wu,
J. Adv. Synth. Catal. 2007, 349, 2151; (b) Sun, X.; Ye, S.; Wu,
J. Eur. J. Org. Chem. 2006, 4787; (c) Wu, J.; Sun, X.; Sun, W.;
Ye, S. Synlett 2006, 2489; (d) Wu, J.; Sun, X.; Sun, W. Org.
Biomol. Chem. 2006, 4, 4231; (e) Wu, J.; Sun, X.; Xia, H.-G.
Tetrahedron Lett. 2006, 47, 1509.
14. Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
15. O’Brien, P.; Rosser, C. M.; Caine, D. Tetrahedron 2003, 59,
9779.
16. Hodgson, D. M.; Stefane, B.; Miles, T. J.; Witherington, J. J.
Org. Chem. 2006, 71, 8510.
2. Mitsunobu, O. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Winterfeldt, E., Eds.; Pergamon: Oxford,
1990; Vol. 7, pp 65–101.
3. Kemp, J. E. G. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Winterfeldt, E., Eds.; Pergamon: Oxford,
1991; Vol. 7, pp 469–512.
4. Murphree, S. S.; Padwa, A. Prog. Heterocycl. Chem. 2001, 13,
52–70.
5. For reviews, see: (a) Pawda, A.; Pearson, W. H.; Lian, B. W.;
Bergmeier, S. C. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: New York, 1996; Vol. 1a, (b) Pawda, A.;
Woolhouse, A. D. In Comprehensive Heterocyclic Chemistry;
Lwowski, W., Ed.; Pergamon: Oxford UK, 1984; Vol. 7, (c)
Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599; (d)
Ibuka, T. Chem. Soc. Rev. 1998, 27, 145; (e) Stamm, H. J.
Prakt. Chem. 1999, 319; (f) Hu, X. E. Tetrahedron 2004, 60,
2701; (g) Ma, L. G.; Xu, J. X. Prog. Chem. 2004, 16, 220; (h)
Rayner, C. M. Synlett 1997, 11; (i) McCoull, W.; Davis, F. A.
Syntheis 2000, 1347; (j) Sweeney, J. B. Chem. Soc. Rev. 2002,
31, 247; (k) Dahanukar, V. H.; Zavialov, L. A. Curr. Opin.
Drug Discovery Dev. 2002, 5, 918.
6. (a) Matsubara, S.; Kodama, T.; Utimoto, K. Tetrahedron
Lett. 1990, 31, 6379; (b) Hayashi, M.; Ono, K.; Hoshimi, H.;
Oguni, N. J. Chem. Soc., Chem. Commun. 1994, 2699; (c)
Hayashi, M.; Ono, K.; Hoshimi, H.; Oguni, N. Tetrahedron
17. (a) Ekegren, J. K.; Roth, P.; Kallstrom, K.; Tarnai, T.;
Andersson, P. G. Org. Biomol. Chem 2003, 1, 358; (b)
Mordini, A.; Russo, F.; Valacchi, M.; Zani, L.; Degl’Inno-
centi, A.; Reginato, G. Tetrahedron 2002, 58, 7153.
18. Tatsuo, O.; Masayuki, N.; Yoriyuki, T.; Yoshiyuki, H. Bull.
Inst. Chem. Res. 1992, 70, 295.
1996, 52, 7817; (d) Muller, P.; Nury, P. Org. Lett. 1999, 1,
¨
439; (e) Li, Z.; Fernandez, M.; Jacobsen, E. N. Org. Lett.
1999, 1, 1611; (f) Mita, T.; Fujimori, I.; Wada, R.; Wen, J.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
11252; (g) Fukuta, Y.; Mita, T.; Fukuta, N.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312; (h) Mita,
T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. Org.
Lett. 2007, 9, 259; (i) Fujimori, I.; Mita, T.; Maki, K.; Shiro,
19. Wu, J.; Hou, X.-L.; Dai, L.-X. J. Chem. Soc., Perkin Trans. 1
2001, 11, 1314.