Asymmetric Michael addition of 4H-thiopyran-4-one to nitroolefins catalyzed by diamine mono-N-sulfonamide and its application to concise synthesis of enantiopure multiring heterocycles

Article abstract of DOI:10.1016/j.tet.2013.05.116

A new series of mono-N-sulfonamides of C₂-symmetrical 2′-bipyrrolidine have been designed, synthesized, and successfully applied as the organocatalysts to the enantio- and diastereoselective Michael addition of 4H-thiopyran-4-one to a variety of nitroolefins. Catalyst 10 was identified in the examinations to exhibit more superior catalytic ability than the traditional chiral pyrrolidine catalysts, giving high chemical yields, excellent diastereo- and enantioselectivities (up to 99:1 dr and 98% ee). The tert-butyl sulfonamide functionality of catalyst 10 is speculated to play crucial roles in the transition state as both bulky group and hydrogen-bond acceptor. Application of a representative Michael adduct has been also studied and proven to be useful for the diversity-oriented synthesis of enantiopure multiring heterocycles through a unique common bicyclic nitrone intermediate.

Full text of DOI:10.1016/j.tet.2013.05.116

Tetrahedron xxx (2013) 1e9
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Tetrahedron
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Asymmetric Michael addition of 4H-thiopyran-4-one to nitroolefins
catalyzed by diamine mono-N-sulfonamide and its application to
concise synthesis of enantiopure multiring heterocycles
*
Lei Mo, Huang Tang, Zhu-Jun Yao
State Key Laboratory of Coordination, Nanjing National Laboratory of Microstructures, School of Chemistry and Chemical Engineering,
Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
a r t i c l e i n f o
a b s t r a c t
A new series of mono-N-sulfonamides of C2-symmetrical 20-bipyrrolidine have been designed, synthe-
sized, and successfully applied as the organocatalysts to the enantio- and diastereoselective Michael
addition of 4H-thiopyran-4-one to a variety of nitroolefins. Catalyst 10 was identified in the examinations
to exhibit more superior catalytic ability than the traditional chiral pyrrolidine catalysts, giving high
chemical yields, excellent diastereo- and enantioselectivities (up to 99:1 dr and 98% ee). The tert-butyl
sulfonamide functionality of catalyst 10 is speculated to play crucial roles in the transition state as both
bulky group and hydrogen-bond acceptor. Application of a representative Michael adduct has been also
studied and proven to be useful for the diversity-oriented synthesis of enantiopure multiring hetero-
cycles through a unique common bicyclic nitrone intermediate.
Article history:
Received 7 April 2013
Received in revised form 21 May 2013
Accepted 24 May 2013
Available online xxx
Keywords:
Organocatalysis
20-Bipyrrolidine
Michael addition
4H-Thiopyran-4-one
Heterocycle
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Based on our recent synthesis of 2-(((S)-2-((S)-1-(pyridin-2-
ylmethyl)pyrrolidin-2-yl)pyrrolidin-1-yl)methyl)pyridine (abbre-
Recent rapid development of the chemical reactions catalyzed by
small organic molecules has made it to be a hot area of organic
chemistry.1 Because of their advantages of environmental friendli-
ness, high efficiency, and excellent selectivity,2 great attentions have
been directed toward the design and application of various orga-
nocatalysts,3 including the frequently used enamine and imine ca-
talysis,4,5 hydrogen-bond activation,6 carbene catalysis,7 and phase-
transfercatalysis8 as well. Asymmetric Michael addition is one of the
most important and frequently used carbonecarbon and carbon-
eheteroatom forming methods.9 Many highly efficient and enan-
tioselective catalytic systems have been developed for the Michael
addition of ketone to nitroolefins after the pioneering works by
List10a and Barbas.10b,10c Several representative catalysts include
Wang’s pyrrolidine sulfonamides11h and thiourea-dehydroabietic
amine,12k Barbas’ diamines,11i Tang’s thiourea-secondary amines,11j
Tsogoeva’s12g,12h and Jacobsen’s primary amine-thioureas,12i Take-
moto’s thiourea-tertiary amine,12l and Chen’s pyrrolidinyl-camphor
derivatives.12t A series of chiral 2,20-bipyrrolidine-type diamine
catalysts were also developed by Alexakis’ group for the asymmetric
Michael addition of ketone to nitroolefins (Fig. 1).10g,11a,11e
viated as (S,S)-PDP, a chiral ligand for Fe(III)),13 we further explored
the organocatalytic application of the mono-N-sulfonamide
* Corresponding author. Tel./fax: þ86 25 8359 3732; e-mail address: yaoz@
nju.edu.cn (Z.-J. Yao).
Fig. 1. Design of chiral 2,20-bipyrrolidine mono-N-sulfonamides.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.116
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2
L. Mo et al. / Tetrahedron xxx (2013) 1e9
derivatives of such a C2-symmytrical 2,20-bipyrrolidine scaffold
(Fig.1). It was initially speculated that multiple nitrogen and oxygen
atoms of the newly introduced sulfonamide functionality might be
able to serve as the electron-donating elements in the catalytic
processes. Herein, we wish to report the highly enantio- and dia-
stereoselective Michael addition of 4H-thiopyran-4-one to nitro-
styrene catalyzed by these newly prepared diamine mono-N-
sulfonamides, and its application to the concise synthesis of enan-
tiopure multiring heterocycles.
Table 1
Catalyst assessment for the asymmetric Michael additiona,b
2. Results and discussion
The new catalysts containing a C2-symmetrical 2,20-bipyrroli-
dine core were conveniently prepared from an intermediate 8 in
our previous synthesis of (S,S)-PDP.13 Starting from tert-butylsul-
fonimide 8, we could easily obtain the corresponding tert-butyl
sulfonamide 9 through m-CPBA oxidation in 90% yield. Selective
deprotection of the N-Boc group of 9 was achieved by treatment
with 0.4 N TFA in CH2Cl2 at 0e20 ꢀC, affording catalyst 10 in 92%
yield. In the other parallel reaction, selective removal of the N-tert-
butylsulfonimide group of 8 was accomplished with 0.2 N TFA in
CH2Cl2 at 0 ꢀC, affording mono-N-Boc-2,20-bipyrrolidine 11 in 93%
yield. Amine 11 could react in parallel with several selected sulfonyl
chlorides in the presence of triethylamine to provide compounds
12aec, respectively. Finally, catalysts 13aec were prepared after
removal of the N-Boc protecting group (Scheme 1).
Entry
Cat.
Additive
Time (d)
Yield (%)
Syn/anti
ee (syn, %)
1
2
3
4
5
6
7
8
10
10
13a
13b
13c
11
d
3
2
2.5
1
5
7
NR
95
98
99
54
56
Trace
Trace
d
d
90
86
85
85
81
d
d
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
50:1
25:1
27:1
31:1
16:1
d
14
15
10
10
d
a
Unless otherwise noted, the reaction was carried out with 4 (1.25 mmol), 5a
(0.25 mmol), catalyst (0.025 mmol), and additive (0.038 mmol) in THF (0.5 ml) at
room temperature.
b
Syn/anti ratio and ee values of the products were determined by chiral HPLC
analysis, and absolute and relative stereochemistry of the products were judged by
comparison with literature works.
Table 2
Examination of solvents and catalyst loadingsa,b
Entry Solvent PhCO2H (mol %) Time (d) Yieldc (%) Syn/anti ee (syn,%)
1
2
3
4
5
6
7
8
DMF
PhMe
DCM
15
15
15
15
15
15
15
1.5
2
3
2
5
5
3
5
3
5
3
7
10
92
90
89
87
71
80
87
81
65:1
67:1
41:1
30:1
57:1
44:1
36:1
33:1
50:1
49:1
59:1
57:1
55:1
91
90
88
88
94
92
90
86
93
93
95
94
94
DCE
MeOH
DMSO
CH3CN
Dioxane 15
9
EtOAc
CHCl3
EtOH
EtOH
EtOH
15
15
15
7.5
3.75
78
85
91
10
11
12d
13e
77 (86f)
69 (84f)
a
Unless otherwise noted, the reaction was carried out with 4 (1.25 mmol), 5a
(0.25 mmol), catalyst 10 (0.025 mmol), and PhCO2H (0.038 mmol) in solvent
(0.5 mL) at room temperature.
Scheme 1. Synthesis of new chiral pyrrolidine catalysts 10, 11, and 13ae13c.
b
Syn/anti ratio and ee values of the products were determined by chiral HPLC
analysis.
c
Isolated yields of the Michael adducts.
With 5 mol % loading of 10.
With 2.5 mol % loading of 10.
Yield based on recovery of the starting material.
d
Michael addition of 4H-thiopyran-4-one (4, a commercially
available and frequently used building block in organic synthesis)
to trans-b-nitrostyrene 5a was chosen as the benchmark reaction to
e
f
examine the catalytic ability of the above newly synthesized cata-
lysts. In the presence of catalytic amount of PhCOOH (15 mol %) as
the additive, all these catalysts 10, 11, 13aec (10 mol %) could effi-
ciently catalyze this reaction to the completion in THF. For com-
parison, two known and frequently used catalysts 14 and 15 were
also applied, and both of them afforded only trace amount of
products. Since catalyst 10 showed the best performance (50:1
dr and 90% ee) in the preliminary assessment (Table 1), it was se-
lected as the catalyst for our further investigations.
A variety of solvents were then examined for an optimal set of
reaction conditions. All the reactions in DMF, toluene, and EtOH
were carried out with better results (Table 2, entries 1, 2, and 11),
and EtOH was selected as the optimal solvent for the next step with
consideration of easy operation and less toxicity. Other solvents
such as DCM, DCE, and CH3CN afforded the products in relatively
lower enantioselectivity and diastereoselectivity. It is noteworthy
here that this reaction also could be carried out well in MeOH and
CHCl3 in longer reaction times (5 days, entries 5 and 10). Under the
optimal conditions, catalyst loading was also examined (entries 12
and 13). It was found that decreasing the catalyst loading would
slow down the reaction rate but shows little effects on the enantio-
and diastereoselectivity and chemical yield of the product. There-
fore, a combination of 10 mol % of catalyst 10 and 15 mol % of ad-
ditive (PhCO2H) in EtOH was finally chosen as the standard
conditions for the further study.
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L. Mo et al. / Tetrahedron xxx (2013) 1e9
3
Under the above optimal conditions, the generality of this re-
action was explored with various nitroolefins 5ae5z (Table 3). The
results showed that all the nitroolefins (5ae5w) having a 2-aryl
substituent (including variously substituted phenyls, 1- or 2-
naphthyl, 2-furyl, and 2-thiophenyl) could give reasonable yields
of Michael adducts with excellent diastereoselectivity (up to 99:1
dr) and enantioselectivity (up to 98% ee). Either electron-
withdrawing or electron-donating groups were well tolerated at
the 2-, 3-, 4- and 6-positions of the phenyl ring of the nitroolefins.
Though the syn/anti ratios of Michael adducts could be varied in
a wide range (7:1e99:1), enantiopurities of the major syn products
were always excellent (ranging from 91% ee to 98% ee). Compared
to the substrates having a 4-halogenated phenyl substituent (en-
tries 2 and 3), the nitroolefins having a 2- and 3-halogenated
phenyl substituent (entries 7, 8, 11, and 12) usually gave better
syn/anti ratios, as well as those having two halogens (entries 15 and
18). Several aliphatic nitroolefins 5xe5z were also tested (entries
24e26). Unfortunately, these three reactions gave no adducts. The
poor electron-withdrawing and charge-stabilizing capacity of the
aliphatic group is speculated to be associated with the disap-
pointing results.
Fig. 2. A proposed catalytic mode.
state with the aid of an acidic additive.11i,14 Such hydrogen-bonding
effect caused by the N-sulfonamide is also thought to be stronger
than that of the N-Boc amide (Table 1, entry 6, catalyst 11). There-
fore, the complete catalytic process could be explained as follows.
The pyrrolidine moiety of catalyst 10 firstly activates the cyclo-
ketone by aid of PhCO2H through the commonly known mecha-
nism to form an enamine intermediate, which will serve as the
Michael donor in the next addition. In the transition state, the tert-
butyl sulfonamide group of catalyst 10 might serve as both a bulky
group and a hydrogen-bond acceptor. These two factors are
thought to direct the favorable orientation of nitrostyrene to re-
ceive the enamine addition from re-face.
Table 3
Asymmetric Michael addition of 4 with various nitroolefinsa,b
These newly synthesized Michael adducts are convenient pre-
cursors for nitrones, which enable quick formation of various five-
membered heterocycles through 1,3-dipolar cycloadditions with
the corresponding dipolarophiles.15 Representatively, treatment of
the Michael adduct 6a with Zn/NH4Cl in THF and water at room
temperature resulted in the formation of a unique bicyclic nitrone
16 as single diastereomer, whose absolute structure was confirmed
by X-ray single crystal analysis. Parallel reactions of nitrone 16 with
methyl acrylate, dimethyl maleate, N-methylmaleimide smoothly
afforded corresponding tricyclic heterocycles 17e19, respectively
(Scheme 2).
Entry
6
Time (d) Yield (%) Syn/anti ee (syn, %)
1
2
3
4
5
6
7
8
6a (R¼C6H5)
3
88
87
83
84
75
83
98
99
73
81
84
86
76
79
98
99
96
96
81
83
85
80
75
NR
NR
NR
59:1
18:1
35:1
22:1
18:1
52:1
41:1
99:1
99:1
52:1
99:1
78:1
7:1
95
93
95
91
93
97
96
96
94
97
98
98
84
97
97
96
97
96
97
98
90
95
94
d
6b (R¼4-ClC6H4)
6c (R¼4-BrC6H4)
6d (R¼4-CF3C6H4)
6e (R¼4-MeOC6H4)
6f (R¼4-MeC6H4)
6g (R¼2-ClC6H4)
6h (R¼2-BrC6H4)
6i (R¼2-MeOC6H4)
6j (R¼2-CF3C6H4)
6k (R¼3-ClC6H4)
6l (R¼3-BrC6H4)
2
1.5
2
5
4
3
2
5
4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3
5
4
6m (R¼3-MeOC6H4)
6n (R¼3-CF3C6H4)
6o (R¼2,4-Cl2C6H3)
6p (R¼2,4-(MeO)2C6H3)
6q (R¼2-Br,4-FC6H3)
6r (R¼2-Cl,6-FC6H3)
6s (R¼piperonyl)
6t (R¼1-naphthyl)
6u (R¼2-naphthyl)
6v (R¼2-furyl)
4
3
3
2
1.5
4
4
4
4
32:1
66:1
55:1
32:1
99:1
15:1
99:1
28:1
25:1
12:1
d
6w (R¼2-thiophenyl)
6x (R¼2-propyl)
6y (R¼tert-butyl)
6z (R¼cyclohexyl)
2
10
10
10
d
d
d
d
a
Unless otherwise noted, the reaction was carried out with 4 (1.25 mmol), 5
(0.25 mmol), catalyst 10 (0.025 mmol), and PhCO2H (0.038 mmol) in EtOH (0.5 mL)
at room temperature.
b
Syn/anti ratios and ee values of the syn-diastereomers were determined by
chiral HPLC analysis.
Scheme 2. 1,3-Dipolar cycloadditions of representative nitrone 16 prepared from
Michael adduct 6a.
In order to explain the observed stereoselectivity, a possible
catalytic mode is proposed (Fig. 2) based on our experimental re-
sults. Because the two structurally similar known proline-derived
catalysts 14 and 15 didn’t work in our examination (Table 1, en-
tries 7 and 8), formation of an extensive hydrogen-bonding net-
work is speculated to take place between the nitro group of the
olefin substrate and the sulfonamide of the catalyst in the transition
3. Conclusion
In summary, a new series of 2,20-bipyrrolidine mono-N-sulfon-
amide organocatalysts have been designed and synthesized.
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4
L. Mo et al. / Tetrahedron xxx (2013) 1e9
Catalyst 10 was identified to exhibit outstanding catalytic ability
under mild conditions, by comparison with two known chiral
pyrrolidine catalysts, in the enantio- and diastereoselective Michael
addition of 4H-thiopyran-4-one to nitroolefins. Introduction of the
tert-butyl sulfonamide group into the catalyst as both a bulky group
and a hydrogen-bond acceptor was proven to be a successful pro-
tocol to direct the favorable orientation of nitrostyrene for the
addition of enamine. The developed catalytic reactions resulted in
high yield of the products with excellent diastereoselectivity (up to
99:1 dr) and enantioselectivity (up to 98% ee). One of the Michael
adducts was successfully converted into a unique bicyclic nitrone
and further applied in the diverse synthesis of enantiopure mul-
tiring heterocycles.
under N2 atmosphere. After being cooled to 0 ꢀC, TFA (0.37 mL,
5.0 mmol) was added slowly. The reaction mixture was stirred at
0
ꢀC for 2 h, and concentrated directly to remove excess TFA. The
residue was purified by silica gel chromatography (CH2Cl2/MeOH/
NH3¼30:1:1) to give 11 (544 mg, 93%) as a yellow solid. Mp
30
104e105 ꢀC. [
a
]
ꢁ57.9 (c 0.50, CHCl3). IR (KBr, nmax): 2979, 1689,
D
1404, 1200, 1171, 1134 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 3.97e3.89
(m, 2H), 3.57e3.52 (m, 1H), 3.42 (dd, J¼5.2, 8.0 Hz, 2H), 3.23e3.16
(m, 1H), 2.28e2.20 (m, 1H), 2.14e1.84 (m, 5H), 1.74e1.62 (m, 2H),
1.47 (s, 1H). 13C NMR (100 MHz, CDCl3):
d 23.4, 24.6, 28.2, 29.1, 29.2,
45.1, 47.5, 60.0, 64.1, 82.4, 158.8. HRMS (MALDI-TOF, m/z) calcd for
C
17H32N2NaO3S ([MþH]þ) 241.1911; found 241.1887.
4.2.3. Synthesis of the chiral catalysts 13ae13c. General procedure
(13a as an example): To a solution of 11 (210 mg, 0.88 mmol) in
CH2Cl2 (5 mL) was added anhydrous triethylamine (0.49 mL,
3.5 mmol) slowly at 0 ꢀC under N2 atmosphere. Then a solution of
TsCl (334 mg, 1.76 mmol) in CH2Cl2 (5 mL) was added to the re-
action, and the mixture was stirred at 0 ꢀC for 2 h. The mixture was
then quenched with aqueous saturated NaHCO3 at 0 ꢀC. The
aqueous phase was extracted with CH2Cl2 for three times. The
combined organic layers were washed with brine and dried over
Na2SO4. Concentration of the solution gave the crude 12a.
Without further purification, the above crude product was
added to a dried flask with CH2Cl2 (7 mL) under N2 atmosphere.
The mixture was cooled to 0 ꢀC and then TFA (0.21 mL, 2.8 mmol)
was added slowly. The reaction mixture was stirred at 0 ꢀC for
30 min and then warmed to room temperature. After being stirred
for 4 h, the mixture was concentrated directly to remove excess
TFA. The residue was purified on silica gel chromatography
(CH2Cl2/MeOH/NH3¼25:1:1) to give 13a (200 mg, 81% for two
steps) as a yellow oil.
4. Experimental section
4.1. General
All reactions were conducted using oven-dried glassware. Tet-
rahydrofuran was dried over Na with benzophenone as indicator.
Toluene, dichloromethane, petroleum ether, and ethyl acetate were
obtained from commercial suppliers and used without further dis-
tillation.1H NMR spectrawere recorded at 300 and 400 MHz, and 13
C
NMR spectra were recorded at corresponding instruments in CDCl3
using TMS as internal standard. IR spectrawere recorded on a Bruker
Vector 22 FTIR instrument. All new compounds were further char-
acterized by HRMS (high resolution mass spectra) or elemental
analysis. Enantiomeric excesses (ees) were determined by chiral
HPLC analysis on an Agilent HP 1200 instrument. Optical rotations
were measured on a Rudolph Autopol III automaticpolarimeter.
4.2. Synthesis of catalysts 9e13c
The procedure for the synthesis of 13b and 13c was analogous.
The common intermediate 8 was prepared according to the
literature.13
d
[
a]
30 ꢁ68.7 (c 1.50, CHCl3). 1H NMR (300 MHz, CDCl3):
4.2.3.1. (2S,20S)-N1-Tosyl-2,20-bipyrrolidine (13a). Yellow oil.
D
1.16 (s, 9H), 1.37e1.56 (m, 9H), 1.63e2.05 (m, 8H), 3.18e3.76 (m,
[
a
]
30 ꢁ101.4 (c 1.01, CHCl3). IR (neat, nmax): 2960, 2877, 1690, 1597,
D
4H), 3.76e4.19 (m, 2H). MS (ESI, m/z): 367.3 [MþNa]þ.
1458, 1341, 1199, 1158, 1091 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
7.74
(d, J¼8.0 Hz, 2H), 7.32 (d, J¼8.0 Hz, 2H), 3.67 (dt, J¼3.6, 8.0 Hz, 1H),
3.45 (s, 1H), 3.40e3.31 (m, 2H), 3.20 (dd, J¼6.8, 15.0 Hz, 1H),
3.13e3.09 (m, 1H), 2.97e2.91 (m, 1H), 2.43 (s, 3H), 1.93e1.71 (m,
4.2.1. (2S,20S)-1-(tert-Butylsulfonyl)-2,20-bipyrrolidine (10). To
a
dried flask was added m-CPBA (70e75%, 1.2 g, 4.8 mmol) and
CH2Cl2 (15 mL) under N2 atmosphere. The mixture was cooled
down to 0 ꢀC, and then 8 (550 mg, 1.6 mmol) in CH2Cl2 (15 mL) was
added slowly via a syringe. The reaction mixture was stirred
overnight at 0 ꢀC and quenched with saturated aqueous Na2S2O3.
The mixture was extracted with CH2Cl2 for three times. After being
washed with saturated aqueous NaHCO3 and brine, the combined
organic layers were dried over Na2SO4 and concentrated.
4H),1.60e1.37 (m, 4H). 13C NMR (100 MHz, CDCl3):
d 21.5, 24.2, 24.9,
28.2, 28.6, 45.8, 49.2, 61.9, 63.8, 127.6, 129.8, 134.8, 143.6. HRMS
(MALDI-TOF, m/z) calcd for C15H23N2O2S ([MþH]þ) 295.1475; found
295.1486.
4.2.3.2. (2S,20S)-N1-((4-Nitrophenyl)sulfonyl)-2,20-bipyrrolidine
(13b). Yellow oil. [
a]
30 ꢁ100.2 (c 0.13, CHCl3). IR (neat, nmax): 2964,
D
Without further purification, crude 9 from above was added to
a dried flask with CH2Cl2 (15 mL) under N2 atmosphere. The mix-
ture was cooled to 0 ꢀC and then TFA (0.45 mL, 6.0 mmol) was
added slowly. The reaction mixture was stirred at 0 ꢀC for 30 min
and warmed to room temperature. After being stirred for 4 h at
room temperature, the reaction mixture was concentrated directly
to remove excess TFA. The residue was purified by silica gel chro-
matography (CH2Cl2/MeOH/NH3¼30:1:1) to give 10 (337 mg, 81%
1685, 1597, 1510, 1306, 1197 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
8.07
(d, J¼9.6 Hz, 2H), 6.76 (d, J¼9.6 Hz, 2H), 3.99e3.95 (m, 1H),
3.59e3.54 (m, 1H), 3.30 (dd, J¼9.6, 17.6 Hz, 1H), 3.21 (dd, J¼8.0,
14.8 Hz, 1H), 3.04e2.99 (m, 1H), 2.82 (dd, J¼7.6, 17.2 Hz, 1H),
2.18e2.01 (m, 2H), 1.98e1.88 (m, 2H), 1.86e1.67 (m, 4H), 1.49e1.40
(m, 1H). 13C NMR (100 MHz, CDCl3):
d 23.4, 24.8, 28.5, 46.5, 49.1,
62.2, 63.4, 111.6, 125.9, 136.8, 153.1. HRMS (MALDI-TOF, m/z) calcd
for C14H20N3O4S ([MþH]þ) 326.1169; found 326.1154.
for two steps) as a white solid. Mp 153e154 ꢀC. [
a
]
28 ꢁ40.8 (c 1.03,
D
CHCl3). IR (KBr, nmax): 2980, 2773, 1419, 1396, 1315, 1198, 1168,
4.2.3.3. (2S,20S)-N1-((3,5-Bis(trifluoromethyl)phenyl)sulfonyl)-
30
1122 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
4.22e4.14 (m, 1H),
2,20-bipyrrolidine (13c). Yellow oil. [
a
]
ꢁ45.2 (c 0.25, CHCl3). IR
D
4.05e3.97 (m, 1H), 3.67e3.51 (m, 2H), 3.39e3.31 (m, 1H), 3.24e3.15
(m, 1H), 2.29e2.17 (m, 2H), 2.11e1.89 (m, 4H), 1.75e1.63 (m, 2H),
(neat, nmax): 2964, 1685, 1597, 1510, 1306, 1197 cmꢁ1
.
1H NMR
(400 MHz, CDCl3):
d
8.40 (s, 2H), 8.08 (s, 1H), 3.80 (dt, J¼3.2, 7.8 Hz,
1.46 (s, 9H). 13C NMR (100 MHz, CDCl3):
d
24.3, 24.9, 25.4, 28.5, 29.6,
1H), 3.44e3.35 (m, 2H), 3.17 (dd, J¼6.8, 14.8 Hz, 1H), 3.08e3.02 (m,
1H), 2.91e2.85 (m, 1H), 2.22 (s, H), 1.92e1.57 (m, 7H), 1.44e1.35 (m,
45.3, 50.8, 61.7, 62.5, 77.1. HRMS (MALDI-TOF, m/z) calcd for
C
12H25N2O2S ([MþH]þ) 261.1631; found 261.1655.
1H). 13C NMR (100 MHz, CDCl3):
d 24.4, 25.2, 28.4, 28.7, 46.2, 49.0,
62.1, 64.9, 121.2, 123.9, 126.0 (m, J¼3.6 Hz), 127.8 (d, J¼2.7 Hz), 132.7
4.2.2. (2S,20S)-tert-Butyl [2,20-bipyrrolidine]-1-carboxylate (11). To
a dried flask was added 8 (840 mg, 2.4 mmol) and CH2Cl2 (25 mL)
(q, J¼4.3 Hz), 144.8. HRMS (MALDI-TOF, m/z) calcd for
C
16H19F6N2O2S ([MþH]þ) 417.1066; found 417.1066.
Please cite this article in press as: Mo, L.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.116

L. Mo et al. / Tetrahedron xxx (2013) 1e9
5
4.3. Synthesis of the Michael adducts 6ae6w
(MALDI-TOF, m/z) calcd for C14H14NF3O3SNa ([MþNa]þ) 356.0539;
found 356.0534. Anal. Calcd for C14H14F3NO3S (%): C 50.45, H 4.23,
N 4.20; found: C 50.34, H 4.19, N 4.21.
General procedure (6a as an example): To a solution of catalyst 10
(6.5 mg, 0.025 mmol) in CH2Cl2 (0.5 mL) was added PhCOOH
(4.5 mg, 0.038 mmol) and 4H-thiopyran-4-one (145 mg,1.25 mmol)
successively at room temperature. Nitroolefin (37 mg, 0.25 mmol)
was then added, and the reaction mixture was stirred for 72 h. The
reaction mixture was quenched with saturated aqueous NH4Cl and
extracted with ethyl acetate for three times. The combined organic
layers were washed with saturated aqueous NaHCO3 and brine,
dried over Na2SO4, and concentrated. Purification on silica gel
chromatography (petroleum ether/ethyl acetate¼6:1e4:1) gave 6a
(59 mg, 91%) as a white solid.
4.3.5. (S)-3-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)dihydro-thio-
pyran-4-one (6e). White solid. Mp 127e129 ꢀC. [
a
]
D
30 ꢁ39.0 (c 0.50,
CHCl3). 93% ee (Chiralpak AD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 254 nm; tR (minor) 14.26 min, tR (major) 39.88 min). IR (KBr,
nmax): 2958, 2924, 1703, 1611, 1583, 1548, 1513, 1430, 1380, 1248,
1177 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
7.42 (d, J¼2.1 Hz, 1H),
7.27e7.17 (m, 2H), 4.86e4.72 (m, 2H), 4.37 (dt, J¼4.5, 10.2 Hz, 1H),
3.30e3.21 (m,1H), 3.01e2.91 (m, 2H), 2.84e2.72 (m, 2H), 2.61e2.50
(m, 2H). 13C NMR (75 MHz, CDCl3):
d 31.4, 35.0, 42.7, 44.4, 55.0, 55.1,
78.7, 114.6, 128.1, 129.1, 159.3, 209.5. HRMS (MALDI-TOF, m/z) calcd
for C14H17N1O4SNa ([MþH]þ) 318.0770; found 318.0792. Anal.
Calcd for C14H17NO4S (%): C 56.93, H 5.80, N 4.74; found: C 56.91, H
5.89, N 4.64.
4.3.1. (S)-3-((R)-2-Nitro-1-phenylethyl)dihydro-thiopyran-4-one
(6a). White solid. Mp 162e163 ꢀC. [
a
]
D
30 ꢁ36.5 (c 0.50, CHCl3). 95%
ee (Chiralpak AS-H; i-PrOH/hexane¼20:80, 1.0 mL/min; 254 nm; tR
(minor) 25.0 min, tR (major) 26.3 min). 1H NMR (400 MHz, CDCl3):
d
7.38e7.28 (m, 3H), 7.21e7.19 (m, 2H), 4.74 (dd, J¼4.8, 12.6 Hz, 1H),
4.3.6. (S)-3-((R)-2-Nitro-1-(p-tolyl)ethyl)dihydro-thiopyran-4-one
30
4.63 (dd, J¼10.0, 12.6 Hz, 1H), 3.98 (dt, J¼4.4, 10.4 Hz, 1H), 3.05 (dt,
J¼4.4, 9.6 Hz, 1H), 3.00e2.96 (m, 2H), 2.90e2.78 (m, 2H), 2.65e2.60
(m, 1H), 2.46 (dd, J¼9.2, 13.6 Hz, 1H). 13C NMR (100 MHz, CDCl3):
(6f). White solid. Mp 101e102 ꢀC. [
a
]
D
ꢁ36.5 (c 0.50, CHCl3). 97%
ee (Chiralpak AD-H; i-PrOH/hexane¼20:80, 1.0 mL/min; 254 nm; tR
(minor) 9.58 min, tR (major) 24.58 min). IR (KBr, nmax): 2922, 1713,
1550, 1431, 1384, 1296, 1193, 1109 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
31.6, 35.1, 43.5, 44.5, 55.0, 78.6, 128.2, 128.3, 136.5, 209.5. HRMS
(MALDI-TOF, m/z) calcd for C13H16NO3S ([MþH]þ) 266.0845; found
266.0845. Anal. Calcd for C13H15NO3S (%): C 58.85, H 5.70, N 5.28;
found: C 51.78, H 6.17, N 5.23.
d
7.14 (d, J¼8.0 Hz, 2H), 7.08 (d, J¼8.0 Hz, 2H), 4.72 (dd, J¼4.4,
12.4 Hz, 1H), 4.60 (dd, J¼9.6, 12.6 Hz, 1H), 3.94 (dt, J¼4.8, 10.4 Hz,
1H), 3.05e2.93 (m, 3H), 2.86e2.75 (m, 2H), 2.64e2.59 (m, 1H), 2.44
(dd, J¼9.2, 13.8 Hz, 1H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3):
4.3.2. (S)-3-((R)-1-(4-Chlorophenyl)-2-nitroethyl)dihydro-thio-
pyran-4-one (6b). White solid. Mp 163e164 ꢀC. [
CHCl3). 93% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 210 nm, tR (minor) 16.51 min, tR (major) 19.50 min). IR (KBr,
nmax): 3032, 2907, 1704, 1546, 1487, 1428, 1380, 1197 cmꢁ1. 1H NMR
d 21.1, 31.6, 35.1, 43.2, 44.5, 55.0, 78.8, 128.0, 130.0, 133.4, 138.0,
a]
30 ꢁ31.7 (c 0.50,
209.6. HRMS (MALDI-TOF, m/z) calcd for C14H18NO3S ([MþH]þ)
280.1002; found 280.0964. Anal. Calcd for C14H17NO3S (%): C 60.19,
H 6.13, N 5.01; found: C 60.18, H 6.14, N 5.04.
D
(400 MHz, CDCl3):
d
7.36e7.32 (m, 2H), 7.17e7.14 (m, 2H), 4.73 (dd,
4.3.7. (S)-3-((R)-1-(2-Chlorophenyl)-2-nitroethyl)dihydro-thio-
J¼4.8, 12.6 Hz, 1H), 4.60 (dd, J¼10.0, 12.6 Hz, 1H), 3.98 (dt, J¼4.4,
pyran-4-one (6g). White solid. Mp 118e119 ꢀC. [
a
]
D
30 ꢁ36.2 (c 0.50,
10.4 Hz, 1H), 3.05e2.96 (m, 3H), 2.89e2.76 (m, 2H), 2.64e2.60 (m,
CHCl3). 96% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 254 nm; tR (minor) 11.32 min, tR (major) 13.07 min). IR (KBr,
nmax): 2918, 1701, 1545, 1476, 1425, 1375, 1219, 1113, 1036 cmꢁ1. 1H
1H), 2.45 (dd, J¼9.2, 13.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 31.6,
35.0, 43.0, 44.5, 54.9, 78.4, 129.5, 129.6, 134.3, 135.0, 209.1. HRMS
(MALDI-TOF, m/z): calcd for C13H15Cl1N1O3S1 [MþH]þ 300.0456;
found 300.0480. Anal. Calcd for C13H14NO3SCl (%): C 52.09, H 4.71, N
4.67; found: C 52.18, H 4.69, N 4.57.
NMR (400 MHz, CDCl3):
d 7.42e7.40 (m, 1H), 7.30e7.22 (m, 3H),
4.86 (dd, J¼9.2, 13.0 Hz, 1H), 4.77 (dd, J¼4.4, 12.8 Hz, 1H), 4.42 (dt,
J¼4.4, 9.8 Hz, 1H), 3.36e3.30 (m, 1H), 3.05e2.93 (m, 2H), 2.88e2.78
(m, 2H), 2.58e2.53 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 31.8, 35.1,
4.3.3. (S)-3-((R)-1-(4-Bromophenyl)-2-nitroethyl)dihydro-thio-
40.5, 45.2, 54.2, 77.3, 127.7, 129.4, 130.7, 134.3, 134.6, 209.1. HRMS
(MALDI-TOF, m/z) calcd for C13H14ClNO3SNa ([MþNa]þ) 322.0275;
found 322.0256. Anal. Calcd for C13H14NO3SCl (%): C 52.09, H 4.71, N
4.67; found: C 51.85, H 4.79, N 4.48.
pyran-4-one (6c). White solid. Mp 179e180 ꢀC. [
a]
30 ꢁ25.6 (c 0.50,
D
CHCl3). 95% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 254 nm; tR (minor) 35.45 min, tR (major) 38.57 min). IR (KBr,
nmax): 2921, 1706, 1548, 1428, 1380, 1196 cmꢁ1. 1H NMR (400 MHz,
CDCl3):
d
7.51e7.47 (m, 2H), 7.11e7.08 (m, 2H), 4.73 (dd, J¼4.4,
4.3.8. (S)-3-((R)-1-(2-Bromophenyl)-2-nitroethyl)dihydro-thio-
12.8 Hz, 1H), 4.60 (dd, J¼10.0, 12.8 Hz, 1H), 3.96 (dt, J¼4.4, 10.4 Hz,
1H), 3.04e2.96 (m, 3H), 2.88e2.78 (m, 2H), 2.63e2.58 (m, 1H), 2.45
pyran-4-one (6h). White solid. Mp 129e131 ꢀC. [
a]
30 ꢁ38.4 (c 0.50,
D
CHCl3). 96% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 254 nm; tR (minor) 13.52 min, tR (major) 15.43 min). IR (KBr,
nmax): 2916, 1694, 1551, 1473, 1437, 1378, 1293, 1112, 1023 cmꢁ1. 1H
(dd, J¼9.6, 14.0 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 31.5, 35.0,
43.0, 44.5, 54.8, 78.3, 122.4, 129.9, 132.5, 135.6, 209.1. HRMS
(MALDI-TOF, m/z) calcd for C13H15BrNO3SNa ([MþNa]þ) 365.9770;
found 365.9780. Anal. Calcd for C13H14NO3SBr (%): C 45.36, H 4.10, N
4.07; found: C 45.46; H 4.16, N 3.98.
NMR (400 MHz, CDCl3):
d
7.60 (dd, J¼1.6, 8.2 Hz, 1H), 7.32 (dt, J¼1.2,
7.4 Hz, 1H), 7.22 (dd, J¼1.6, 8.0 Hz, 1H), 7.16 (dt, J¼1.6, 7.6 Hz, 1H),
4.86e4.76 (m, 2H), 4.48e4.45 (m, 1H), 3.32 (s, 1H), 3.06e2.94 (m,
2H), 2.86e2.81 (m, 2H), 2.66e2.52 (m, 2H). 13C NMR (100 MHz,
4.3.4. (S)-3-((R)-2-Nitro-1-(4-(trifluoromethyl)phenyl)ethyl)dihy-
CDCl3): d 31.8, 35.1, 42.4, 45.3, 54.6, 77.2, 128.4, 129.6, 134.0, 136.1,
dro-thiopyran-4-one (6d). White solid. Mp 191e192 ꢀC. [
a
]
D
30 ꢁ30.6
209.1. HRMS (MALDI-TOF, m/z) calcd for C13H15BrNO3SNa
(c 0.50, CHCl3). 91% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80,
1.0 mL/min; 254 nm; tR (minor) 14.84 min, tR (major) 22.98 min). IR
(KBr, nmax): 2922, 1707, 1551, 1380, 1330, 1219, 1120, 772 cmꢁ1. 1H
([MþNa]þ) 365.9770; found 365.9799. Anal. Calcd for
C13H14NO3SBr (%): C 45.36, H 4.10, N 4.07; found: C 45.47, H 4.16, N
4.01.
NMR (400 MHz, CDCl3):
d
7.63 (d, J¼8.4 Hz, 1H), 7.36 (d, J¼8.0 Hz,
1H), 4.78 (dd, J¼4.4, 13.0 Hz, 1H), 4.66 (dd, J¼10.0, 13.0 Hz, 1H), 4.08
(dt, J¼4.8, 10.2 Hz, 1H), 3.11e2.97 (m, 3H), 2.90e2.80 (m, 2H),
2.61e2.56 (m, 1H), 2.46 (dd, J¼9.6, 14.0 Hz, 1H). 13C NMR (100 MHz,
4.3.9. (S)-3-((R)-1-(2-Methoxyphenyl)-2-nitroethyl)dihydro-thio-
30
pyran-4-one (6i). White solid. Mp 78e80 ꢀC. [
a
]
D
ꢁ41.0 (c 0.50,
CHCl3). 94% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 254 nm; tR (minor) 9.69 min, tR (major) 10.64 min). IR (KBr,
nmax): 2922, 1701, 1546, 1491, 1376, 1220, 1108, 1019 cmꢁ1. 1H NMR
CDCl3):
d 31.6, 35.0, 43.3, 44.6, 54.8, 78.1, 122.4, 125.1, 126.3 (dd,
J¼3.6, 8.2 Hz), 130.5 (q, J¼2.5 Hz), 130.8, 140.8, 208.8. HRMS
Please cite this article in press as: Mo, L.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.116

6
L. Mo et al. / Tetrahedron xxx (2013) 1e9
(400 MHz, CDCl3):
d
7.26 (dt, J¼1.2, 8 Hz, 1H), 7.42e7.40 (d,
C
C
14H17N1O4SNa ([MþH]þ) 318.0770; found 318.0783. Anal. Calcd for
J¼6.8 Hz, 1H), 6.90 (t, J¼7.2 Hz, 2H), 4.84 (dd, J¼9.6, 12.4 Hz, 1H),
4.67 (dd, J¼4.4, 12.4 Hz, 1H), 4.12 (dt, J¼4.4, 10.4 Hz, 1H), 3.85 (s,
3H), 3.37 (dt, J¼4.4, 10.2 Hz, 1H), 2.94e2.90 (m, 2H), 2.87e2.76 (m,
2H), 2.58e2.53 (m, 1H), 2.44 (dd, J¼9.6, 13.8 Hz, 1H). 13C NMR
14H17NO4S (%): C 56.93, H 5.80, N 4.74; found: C 56.73, H 5.87, N 4.75.
4.3.14. (S)-3-((R)-2-Nitro-1-(3-(trifluoromethyl)phenyl)ethyl)dihy-
dro-thiopyran-4-one (6n). White solid. Mp 77e78 ꢀC. [
0.50, CHCl3). 97% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80,
1.0 mL/min; 254 nm; tR (minor) 13.39 min, tR (major) 14.19 min). IR
(KBr, nmax): 2923, 1708, 1551, 1427, 1329, 1163, 1120, 1075 cmꢁ1. 1H
a
]
30 ꢁ32.3 (c
D
(100 MHz, CDCl3):
d
31.6, 35.3, 41.2, 44.7, 53.0, 55.4, 77.1, 111.3, 121.1,
124.1, 129.5, 131.4, 157.6, 210.0. HRMS (MALDI-TOF, m/z) calcd for
C
14H17N1O4SNa ([MþH]þ) 318.0770; found 318.0796. Anal. Calcd
for C14H17NO4S (%): C 56.93, H 5.80, N 4.74; found: C 56.79, H 5.65, N
4.66.
NMR (400 MHz, CDCl3):
d
7.58 (d, J¼7.6 Hz, 1H), 7.52e7.48 (m, 2H),
7.43 (d, J¼8.0 Hz, 1H), 4.78 (dd, J¼4.4, 12.8 Hz, 1H), 4.66 (dd, J¼10.0,
13.0 Hz, 1H), 4.08 (dt, J¼4.4, 10.4 Hz, 1H), 3.11e2.97 (m, 3H),
2.90e2.78 (m, 2H), 2.60e2.56 (m, 1H), 2.46 (dd, J¼9.6, 13.6 Hz, 1H).
4.3.10. (S)-3-((R)-2-Nitro-1-(2-(trifluoromethyl)phenyl)ethyl)dihy-
dro-thiopyran-4-one (6j). White solid. Mp 147e149 ꢀC. [
25
a]
ꢁ11.3
13C NMR (100 MHz, CDCl3):
d 31.5, 35.0, 43.4, 44.6, 54.8, 78.1, 122.4,
D
(c 0.20, CHCl3). 97% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80,
125.0 (dd, J¼4.6, 8.2 Hz),125.3 (q, J¼3.6 Hz),129.9,131.5, 131.6,131.8
1.0 mL/min; 254 nm; tR (minor) 8.72 min, tR (major) 9.78 min). IR
(q, J¼32.5 Hz), 137.8, 208.8. HRMS (MALDI-TOF, m/z) calcd for
(KBr, nmax): 2922, 1701, 1551, 1427, 1309, 1111, 1035, 770 cmꢁ1
.
1H
C
14H15NF3O3S ([MþH]þ) 334.0719, found 334.0735. Anal. Calcd
NMR (400 MHz, CDCl3):
d
7.72 (d, J¼8.0 Hz, 1H), 7.59 (t, J¼7.6 Hz,
for C14H14F3NO3S (%): C 50.45, H 4.23, N 4.20; found: C 50.32, H
4.44, N 4.18.
1H), 7.44 (t, J¼7.6 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H), 4.93 (dd, J¼7.2,
12.0 Hz, 1H), 4.69 (dd, J¼4.4, 11.8 Hz, 1H), 4.20e4.15 (m, 1H), 3.46
(dt, J¼4.4, 11.0 Hz, 1H), 3.08e2.83 (m, 4H), 2.60e2.54 (m, 1H),
4.3.15. (S)-3-((R)-1-(2,4-Dichlorophenyl)-2-nitroethyl)dihydro-thio-
pyran-4-one (6o). White solid. Mp 97e98 ꢀC. [
30
2.44e2.39 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
32.1, 35.7, 38.6,
a]
ꢁ33.7 (c 0.50,
D
45.6, 55.2, 78.3, 122.7, 125.4, 126.9 (q, J¼5.5 Hz), 128.1, 128.3, 129.5
CHCl3). 97% ee (Chiralpak OD-H; i-PrOH/hexane¼7:93, 1.0 mL/min;
(q, J¼29.8 Hz), 132.9, 136.0, 209.1. HRMS (MALDI-TOF, m/z) calcd for
254 nm; tR (minor) 28.52 min, tR (major) 36.72 min). IR (KBr, nmax):
C
C
14H15NF3O3S ([MþH]þ) 334.0719, found 334.0733. Anal. Calcd for
2919, 1708, 1552, 1475, 1426, 1377, 1106, 816 cmꢁ1 1H NMR
.
14H14F3NO3S (%): C 50.45, H 4.23, N 4.20; found: C 50.37, H 4.39, N
(400 MHz, CDCl3):
d
7.44 (d, J¼2.0 Hz, 1H), 7.27 (dd, J¼2.0, 8.4 Hz,
4.18.
1H), 7.19 (d, J¼8.4 Hz, 1H), 4.84 (dd, J¼9.2, 12.8 Hz, 1H), 4.76 (dd,
J¼4.4, 12.8 Hz, 1H), 4.38 (dt, J¼4.0, 10.0 Hz, 1H), 3.05e2.95 (m, 2H),
2.87e2.78 (m, 2H), 2.62e2.54 (m, 2H). 13C NMR (100 MHz, CDCl3):
4.3.11. (S)-3-((R)-1-(3-Chlorophenyl)-2-nitroethyl)dihydro-thio-
pyran-4-one (6k). White solid. Mp 74e75 ꢀC. [
CHCl3). 98% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 254 nm; tR (minor) 17.40 min, tR (major) 18.58 min). IR (KBr,
nmax): 2922, 2853, 1707, 1553, 1433, 1378, 1306, 1117, 797 cmꢁ1. 1H
30
a
]
ꢁ33.8 (c 0.50,
d 31.8, 35.1, 40.2, 45.2, 54.1, 77.2, 128.1, 130.5, 133.0, 134.7, 135.3,
D
208.8. HRMS (MALDI-TOF, m/z) calcd for C13H14Cl2NO3S ([MþH]þ)
334.0066; found 334.0088. Anal. Calcd for C13H13Cl2NO3S (%): C
55.34, H 4.64, N 3.40; found: C 55.12, H 4.62, N 3.63.
NMR (300 MHz, CDCl3): d 7.33e7.26 (m, 2H), 7.21 (m, 1H), 7.14e7.07
(m, 1H), 4.74 (dd, J¼4.5, 12.6 Hz, 1H), 4.60 (dd, J¼9.9, 12.8 Hz, 1H),
3.97 (dt, J¼4.5, 10.2 Hz, 1H), 3.07e2.94 (m, 3H), 2.90e2.74 (m, 2H),
2.64e2.58 (m, 1H), 2.47 (dd, J¼9.3, 13.8 Hz, 1H). 13C NMR (75 MHz,
4.3.16. (S)-3-((R)-1-(2,4-Dimethoxyphenyl)-2-nitroethyl)dihydro-
30
thiopyran-4-one (6p). Yellow solid. Mp 88e89 ꢀC. [
a]
ꢁ39.0 (c
D
0.50, CHCl3). 96% ee (Chiralpak AD-H; i-PrOH/hexane¼20:80,
1.0 mL/min; 254 nm; tR (minor) 10.93 min, tR (major) 14.48 min). IR
(KBr, nmax): 2922, 2837, 1706, 1611, 1551, 1437, 1288, 1209, 1158,
CDCl3):
d 31.6, 35.1, 43.2, 44.6, 54.8, 78.2, 126.4, 128.4, 128.6, 130.6,
135.2, 138.7, 209.0. HRMS (MALDI-TOF, m/z) calcd for C13H15ClNO3S
([MþH]þ) 300.0456; found 300.0464. Anal. Calcd for C13H14NO3SCl
(%): C 52.09, H 4.71, N 4.67; found: C 51.85, H 5.07, N 4.36.
1031, 771 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
7.00 (d, J¼8.4 Hz, 1H),
6.44e6.38 (m, 2H), 4.79 (dd, J¼9.6, 12.3 Hz, 1H), 4.62 (dd, J¼4.5,
12.3 Hz, 1H), 4.02 (dt, J¼4.5, 10.5 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H),
3.30 (dt, J¼4.5, 10.2 Hz, 1H), 2.96e2.71 (m, 4H), 2.60e2.54 (m, 1H),
4.3.12. (S)-3-((R)-1-(3-Bromophenyl)-2-nitroethyl)dihydro-thio-
30
pyran-4-one (6l). White solid. Mp 70e71 ꢀC. [
a]
D
ꢁ35.4 (c 0.50,
2.42 (dd, J¼9.9,13.8 Hz). 13C NMR (75 MHz, CDCl3):
d 31.4, 35.2, 40.7,
CHCl3). 98% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/min;
44.5, 52.9, 55.2, 55.3, 77.2, 99.2, 104.6, 116.1, 131.8, 158.4, 160.7,
210.0. HRMS (MALDI-TOF, m/z) calcd for C15H20NO5S ([MþH]þ)
326.1057; found 326.1062.
254 nm; tR (minor) 14.98 min, tR (major) 16.12 min). IR (KBr, nmax):
2921, 2853, 1704, 1549, 1478, 1432, 1219, 1083 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d 7.30e7.29 (m, 2H), 7.22e7.21 (m, 1H), 7.12e7.09
(m,1H), 4.74 (dd, J¼4.5,12.6 Hz,1H), 4.60 (dd, J¼9.9,12.8 Hz,1H), 3.97
(dt, J¼4.5, 10.2 Hz, 1H), 3.07e2.97 (m, 3H), 2.90e2.74 (m, 2H),
2.64e2.58 (m, 1H), 2.47 (dd, J¼9.6, 14.0 Hz, 1H); 13C NMR (100 MHz,
4.3.17. (S)-3-((R)-1-(2-Bromo-4-fluorophenyl)-2-nitroethyl)dihydro-
25
thiopyran-4-one (6q). White solid. Mp 117e119 ꢀC. [
a
]
ꢁ36.1 (c
D
0.20, CHCl3). 97% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80,
1.0 mL/min; 254 nm; tR (minor) 12.96 min, tR (major) 15.15 min). IR
(KBr, nmax): 2920, 2850, 1702, 1597, 1547, 1486, 1375, 1219, 858,
CDCl3):
d 31.6, 35.1, 43.2, 44.6, 54.8, 78.2, 126.4, 128.4, 128.6, 130.6,
135.2,138.7,209.0.HRMS(MALDI-TOF,m/z)calcdforC13H15BrNO3SNa
([MþNa]þ) 365.9770; found 365.9793. Anal. Calcd for C13H14NO3SBr
(%): C 45.36, H 4.10, N 4.07; found: C 45.74, H 4.42, N 4.34.
772 cmꢁ1. 1H NMR (400 MHz, CDCl3):
7.23 (dd, J¼6.0, 8.8 Hz, 1H), 7.07 (dt, J¼2.8, 7.8 Hz, 1H), 4.86e4.75
(m, 2H), 4.45e4.39 (m, 1H), 3.26 (s, 1H), 3.06e2.93 (m, 2H),
2.86e2.76 (m, 2H), 2.65e2.52 (m, 2H). 13C NMR (100 MHz, CDCl3):
d
7.36 (dd, J¼2.4, 8.2 Hz, 1H),
4.3.13. (S)-3-((R)-1-(3-Methoxyphenyl)-2-nitroethyl)dihydro-thio-
pyran-4-one (6m). White solid. Mp 129e130 ꢀC. [
a]
D
30 ꢁ31.1 (c 0.50,
d
31.8, 35.0, 41.4, 41.8, 45.2, 54.7, 77.2, 115.6 (d, J¼20.7 Hz), 121.1 (d,
CHCl3). 84% ee (Chiralpak AD-H; i-PrOH/hexane¼20:80, 1.0 mL/min;
J¼24.3 Hz), 125.6, 129.8, 132.2, 160.3, 162.8, 208.9. HRMS (MALDI-
TOF, m/z): calcd for C13H14BrFNO3S ([MþH]þ) 361.9856; found
361.9850. Anal. Calcd for C13H13BrFNO3S (%): C 43.11, H 3.62, N 3.87;
found: C 43.13, H 3.63, N 3.83.
254 nm; tR (minor) 12.47 min, tR (major) 18.49 min). IR (KBr, nmax):
2922, 2852, 1699, 1601, 1489, 1379, 1250, 1051 cmꢁ1 1H NMR
.
(400 MHz, CDCl3): d 7.28e7.24 (m, 1H), 6.84e6.74 (m, 3H), 4.73 (dd,
J¼4.4, 12.6 Hz, 1H), 4.62 (dd, J¼9.6, 12.8 Hz, 1H), 3.94 (dt, J¼4.4,
10.4 Hz, 1H), 3.79 (s, 3H), 3.05e2.93 (m, 3H), 2.88e2.75 (m, 2H),
2.66e2.62 (m, 1H), 2.47 (dd, J¼9.6, 13.8 Hz, 1H). 13C NMR (100 MHz,
4.3.18. (S)-3-((R)-1-(2-Chloro-6-fluorophenyl)-2-nitroethyl)dihydro-
25
thiopyran-4-one (6r). White solid. Mp 131e133 ꢀC. [
a]
ꢁ64.4 (c
D
CDCl3):
d
31.6, 35.1, 43.5, 44.5, 55.0, 55.2, 78.5, 113.2, 114.5, 120.2,
0.10, CHCl3). 96% ee (Chiralpak OD-H; i-PrOH/hexane¼10:90,
130.4, 138.1, 160.1, 209.5. HRMS (MALDI-TOF, m/z) calcd for
1.0 mL/min; 254 nm; tR (minor) 14.53 min, tR (major) 17.69 min). IR
Please cite this article in press as: Mo, L.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.116

L. Mo et al. / Tetrahedron xxx (2013) 1e9
7
(KBr, nmax): 2957, 2923, 2853, 1709, 1552, 1454, 1378, 1245, 1115,
881, 780 cmꢁ1 1H NMR (400 MHz, CDCl3):
7.28e7.22 (m, 2H),
7.06e7.01 (m, 1H), 4.86e4.72 (m, 3H), 3.32 (s, 1H), 3.05e2.89 (m,
2H), 2.88e2.77 (m, 2H), 2.63e2.57 (m, 1H), 2.49e2.44 (m, 1H). 13
NMR (100 MHz, CDCl3): 31.6, 34.9, 37.8, 45.2, 53.0, 76.3, 115.1 (d,
J¼23.6 Hz), 122.8 (d, J¼10.0 Hz), 126.5, 130.1, 136.8, 160.6, 163.1,
208.6. HRMS (MALDI-TOF, m/z): calcd for C13H14ClFNO3S ([MþH]þ)
318.0361; found 318.0335. Anal. Calcd for C13H13ClFNO3S (%): C
49.14, H 4.12, N 4.41; found: C 49.25, H 4.25, N 4.31.
for C11H13NO4S (%): C 51.75, H 5.13, N 5.49; found: C 51.71, H 5.17,
N 5.29.
.
d
C
4.3.23. (S)-3-((S)-2-Nitro-1-(thiophen-2-yl)ethyl)dihydro-thio-
d
pyran-4-one (6w). Yellow solid. Mp 109e110 ꢀC. [
a
]
30 ꢁ34.3 (c 0.50,
D
CHCl3). 94% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 254 nm; tR (minor) 15.68 min, tR (major) 18.36 min). IR (KBr,
nmax): 2923, 1701, 1546, 1425, 1376, 1219, 771, 698 cmꢁ1 1H NMR
.
(400 MHz, CDCl3):
d
7.26 (d, J¼5.6 Hz, 1H), 6.97e6.93 (m, 2H), 4.74
(dd, J¼4.4, 12.6 Hz, 1H), 4.64 (dd, J¼9.6, 12.6 Hz, 1H), 4.32 (dt, J¼4.4,
9.4 Hz, 1H), 3.08e2.96 (m, 3H), 2.86e2.74 (m, 3H), 2.56 (dd, J¼10.0,
4.3.19. (S)-3-((R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl)dihydro-
13.6 Hz). 13C NMR (100 MHz, CDCl3):
d 31.5, 34.9, 39.0, 44.6, 55.8,
30
thiopyran-4-one (6s). White solid. Mp 149e150 ꢀC. [
a
]
ꢁ29.6 (c
D
79.0, 125.6, 127.2, 127.3, 139.1, 208.9. HRMS (MALDI-TOF, m/z) calcd
for C11H13NNaO3S2 ([MþNa]þ) 294.0229; found 294.0230. Anal.
Calcd for C11H13NO3S2 (%): C 48.69, H 4.83, N 5.16; found: C 48.71, H
4.87, N 5.11.
0.50, CHCl3). 97% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80,
1.0 mL/min; 254 nm; tR (minor) 25.80 min, tR (major) 26.64 min).
IR (KBr, nmax): 3278, 3626, 2922, 2852, 1701, 1547, 1484, 1375,
1242, 1034 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
6.76 (d, J¼8.1 Hz,
1H), 6.67e6.64 (m, 2H), 5.96 (s, 2H), 4.70 (dd, J¼4.5, 12.6 Hz, 1H),
4.54 (dd, J¼9.9, 12.4 Hz, 1H), 3.90 (dt, J¼4.5, 10.2 Hz, 1H),
3.00e2.65 (m, 6H), 2.48 (dd, J¼9.0, 13.6 Hz, 1H). 13C NMR
4.4. Procedure for 1,3-dipolar cycloadditions
4.4.1. (3R,3aS)-3-Phenyl-2,3,3a,4,6,7-hexahydrothiopyrano[4,3-b]
pyrrole 1-oxide (16). A suspension of 6a (265 mg, 1 mmol), zinc
dust (650 mg, 10 mmol), and NH4Cl (50 mg, 0.9 mmol) in THF
(5 mL) and H2O (2 mL) was stirred at room temperature under N2
atmosphere for 12 h. The mixture was filtrated through a pad of
Celite, and the filtration was concentrated in vacuo. The residue was
purified by column chromatography on silica gel (CH2Cl2/MeOH/
(100 MHz, CDCl3):
d 31.6, 35.1, 43.3, 44.5, 55.1, 78.7, 101.4, 108.0,
108.9, 121.8, 129.9, 147.6, 148.4, 209.5. HRMS (MALDI-TOF, m/z)
calcd for C14H16NO5S ([MþH]þ) 310.0744; found 310.0718. Anal.
Calcd for C14H15NO5S (%): C 54.36, H 4.89, N 4.53; found: C 54.16,
H 5.02, N 4.42.
4.3.20. (S)-3-((R)-1-(Naphthalen-1-yl)-2-nitroethyl)dihydro-thio-
NH3¼30:1:1) to afford 16 (203 mg, 87%) as a brown solid. Mp
pyran-4-one (6t). White solid. Mp 126e128 ꢀC. [
a]
30 ꢁ79.6 (c 0.50,
D
25
187e188 ꢀC. [
a
]
ꢁ56.6 (c 0.10, CHCl3). IR (KBr, nmax): 2921, 2852,
D
CHCl3). 98% ee (Chiralpak AS-H; i-PrOH/hexane¼20:80,1.0 mL/min;
1605, 1457, 1235, 769 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 7.38e7.22
254 nm; tR (minor) 22.09 min, tR (major) 29.22 min). IR (KBr, nmax):
(m, 5H), 4.30e4.21 (m, 1H), 4.17e4.07 (m, 1H), 3.57e3.52 (m, 1H),
3.27e3.09 (m, 2H), 2.86e2.74 (m, 2H), 2.66 (dt, J¼3.3, 12.6 Hz, 1H),
2.53 (dd, J¼11.1, 13.0 Hz, 1H), 2.42e2.31 (m, 1H). 13C NMR (100 MHz,
3052, 2917, 1698, 1548, 1427, 1376, 1304, 1117, 787 cmꢁ1 1H NMR
.
(300 MHz, CDCl3)
d
8.23 (d, J¼6.9 Hz, 1H), 7.84 (dd, J¼8.1, 20.6 Hz,
2H), 7.60e7.40 (m, 4H), 4.97e4.85 (m, 3H), 3.24 (s, 1H), 2.97e2.78
CDCl3):
d 25.3, 26.2, 33.0, 44.5, 50.6, 66.8, 126.3, 126.8, 128.2, 137.8.
(m, 4H), 2.45 (dd, J¼7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d 31.7,
HRMS (MALDI-TOF, m/z) calcd for C13H16NOS ([MþH]þ) 234.0947;
35.1, 36.3, 44.8, 56.3, 78.6, 122.7, 123.8, 125.5, 125.8, 126.0, 126.8,
128.6, 129.1, 132.3, 133.5, 134.0, 209.7. HRMS (MALDI-TOF, m/z)
calcd for C17H18NO3S ([MþH]þ) 316.1002; found 316.1020. Anal.
Calcd for C17H17NO3S (%): C 64.74, H 5.43, N 4.44; found: C 64.65, H
5.48, N 4.42.
found 234.0964.
4.4.2. Synthesis of the 1,3-dipolar cycloaddition adducts 17e20 (us-
ing 20 as an example). A solution of 16 (23 mg, 0.1 mmol) and N-
methylmaleimide (111 mg, 1 mmol) in toluene (3 mL) was stirred at
room temperature under N2 atmosphere for 15 min. The reaction
mixture was then heated to reflux for 4 h. The solution was cooled
down to room temperature and concentrated directly. The residue
was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate¼3:1) to afford 20a (15 mg, 50%) and 20b (11 mg,
33%).
4.3.21. (S)-3-((R)-1-(Naphthalen-2-yl)-2-nitroethyl)dihydro-thio-
pyran-4-one (6u). White solid. Mp 144e146 ꢀC. [
CHCl3). 90% ee (Chiralpak OD-H; i-PrOH/hexane¼20:80, 1.0 mL/
min; 254 nm; tR (minor) 24.72 min, tR (major) 54.15 min). IR (KBr,
nmax): 3058, 2921, 1704, 1552, 1431, 1379, 1307, 1224, 1114 cmꢁ1. 1H
a
]
30 ꢁ30.4 (c 0.50,
D
NMR (400 MHz, CDCl3): d 7.85e7.78 (m, 3H), 7.67 (s, 1H), 7.52e7.46
(m, 2H), 7.30 (dd, J¼1.5, 8.4 Hz, 1H), 4.81 (dd, J¼4.4, 12.8 Hz, 1H),
4.72 (dd, J¼10.0, 12.6 Hz, 1H), 4.16 (dt, J¼4.4, 10.2 Hz, 1H), 3.13 (dt,
J¼4.4, 9.4 Hz, 1H), 3.00e2.75 (m, 4H), 2.62e2.57 (m, 1H), 2.46 (dd,
4.4.2.1. (6R,6aS,10aS)-Methyl-6-phenyloctahydrothiopyrano
[40,30:2,3]pyrrolo[1,2-b]isoxazole-2-carboxylate (17). Colorless oil
(inseparable diastereomeric mixture, dr¼1:1). [
a]
24 ꢁ105.6 (c 0.50,
D
J¼9.2, 13.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 31.5, 35.2, 43.7,
CHCl3). IR (neat, nmax): 2923, 2852, 1734, 1457, 1207, 1015 cmꢁ1. 1H
44.6, 54.9, 78.6, 124.8, 126.5, 126.7, 127.7, 127.9, 128.1, 129.4, 133.0,
133.4, 133.8, 209.4. HRMS (MALDI-TOF, m/z) calcd for C17H18NO3S
([MþH]þ) 316.1002; found 316.1015. Anal. Calcd for C17H17NO3S (%):
C 64.74, H 5.43, N 4.44; found: C 64.53, H 5.52, N 4.24.
NMR (400 MHz, CDCl3):
d 7.40e7.29 (m, 4H), 7.24e7.20 (m, 1H),
4.75e4.68 (m, 1H), 3.85e3.75 (m, 5H), 3.58e3.50 (m, 1H), 2.86 (dt,
J¼4.0, 14.0 Hz), 2.72e2.31 (m, 6H), 1.94e1.80 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 26.1, 26.2, 26.3, 26.4, 31.8, 32.0, 43.4, 43.3, 47.7,
47.8, 50.2, 50.7, 52.4, 52.7, 60.7, 60.8, 73.6, 73.9, 74.4, 75.2, 77.2,
126.7, 128.1, 128.2, 128.8, 142.4, 142.5, 171.2, 172.8. HRMS (MALDI-
TOF, m/z) calcd for C17H22NO3S ([MþH]þ) 320.1315; found 320.1307.
4.3.22. (S)-3-((S)-1-(Furan-2-yl)-2-nitroethyl)dihydro-thiopyran-4-
30
one (6v). White solid. Mp 105e107 ꢀC. [
a
]
ꢁ17.3 (c 0.50, CHCl3).
D
95% ee (Chiralpak OD-H; i-PrOH/hexane¼10:90, 1.0 mL/min;
254 nm; tR (minor) 18.24 min, tR (major) 19.19 min). IR (KBr,
4.4.2.2. (1S,2R,6R,6aS,10aR)-Dimethyl-6-phenyloctahydrothio-
nmax): 2923, 1707, 1553, 1383, 1190, 1116, 915 cmꢁ1 1H NMR
.
pyrano[40,30:2,3]pyrrolo[1,2-b]isoxazole-1,2-dicarboxylate
28
(300 MHz, CDCl3):
d
7.37 (d, J¼1.2 Hz, 1H), 6.31e6.24 (m, 2H),
(18a). Colorless oil. [
a
]
D
ꢁ63.3 (c 0.25, CHCl3). IR (neat, nmax):
2926, 2852, 1719, 1453, 1218, 1071 cmꢁ1. 1H NMR (400 MHz, CDCl3):
4.68e4.64 (m, 2H), 4.16e4.08 (m, 1H), 3.12 (dt, J¼4.8, 9.9 Hz, 1H),
2.99e2.94 (m, 2H), 2.85e2.74 (m, 2H), 2.64e2.48 (m, 2H). 13C
d
7.35e7.29 (m, 4H), 7.25e7.21 (m, 1H), 4.99 (d, J¼8.8 Hz, 1H),
NMR (75 MHz, CDCl3):
d 31.2, 34.5, 37.2, 44.6, 53.4, 76.2, 109.7,
3.90e3.82 (m, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.64 (td, J¼5.2, 9.4 Hz,
1H), 2.97 (dd, J¼3.6, 14.6 Hz, 1H), 2.72e2.65 (m, 1H), 2.59e2.49 (m,
2H), 2.36e2.32 (m, 1H), 1.91e1.76 (m, 2H). 13C NMR (100 MHz,
110.4, 142.8, 149.5, 208.4. HRMS (MALDI-TOF, m/z) calcd for
C
11H13NNaO4S ([MþNa]þ) 278.0457; found 278.0449. Anal. Calcd
Please cite this article in press as: Mo, L.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.116

8
L. Mo et al. / Tetrahedron xxx (2013) 1e9
2. (a) Luo, C. H.; Du, D. M. Synthesis 2011, 1968e1973; (b) Mase, N.; Barbas, C. F.
CDCl3):
d 25.1, 26.2, 28.0, 46.4, 51.9, 52.3, 52.7, 57.9, 61.2, 75.8, 76.4,
Org. Biomol. Chem. 2010, 8, 4043e4050; (c) Hernandez, J. G.; Juaristi, E. Chem.
Commun. 2012, 5396e5409.
126.9, 128.1, 128.9, 142.4, 169.7, 170.7. HRMS (MALDI-TOF) calcd for
C
19H23NO5SNa ([MþNa]þ) 400.1189; found 400.1173.
3. For recent reviews, see: (a) Dalko, P. I. Angew. Chem., Int. Ed. 2004, 43,
5138e5175; (b) Dalko, P. I. Enantioselective Organo-catalysis; Wiley-VCH:
Weinheim, Germany, 2007.
4. Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471e5569.
4.4.2.3. (1R,2S,6R,6aS,10aR)-Dimethyl-6-phenyloctahydrothio-?
tjl]pyrano[40,30:2,3]pyrrolo[1,2-b]isoxazole-1,2-dicarboxylate
24 ꢁ90.0 (c 0.33, CHCl3). IR (neat, nmax): 2923,
5. For selected imine-catalyzed reactions, see: (a) Zhang, H.; Wen, X. J.; Gan, L. H.;
Peng, Y. G. Org. Lett. 2012, 14, 2126e2129; (b) Kano, T.; Sakamoto, R.; Akakura,
M.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 7516e7520; (c) Galzerano, P.;
Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009,
(18b). Colorless oil. [
a
]
D
2852, 1736, 1458, 1208, 1074 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
7.35e7.32 (m, 2H), 7.27e7.24 (m, 1H), 7.21e7.19 (m, 2H), 3.88 (s,
ꢀ
3H), 3.87 (s, 3H), 3.60 (dd, J¼10.0, 13.6 Hz, 1H), 3.50 (dd, J¼9.6,
13.6 Hz, 1H), 3.29 (dd, J¼3.6, 14.4 Hz, 1H), 3.23 (dd, J¼2.8, 9.8 Hz,
1H), 3.01 (t, 12.4 Hz), 2.63e2.50 (m, 3H), 2.36 (dd, J¼3.2, 13.2 Hz,
48, 7892e7894; (d) Franzen, J.; Fisher, A. Angew. Chem., Int. Ed. 2009, 48,
787e791.
6. For selected hydrogen-bond activated reactions, see: (a) Zhang, Y.; Liu, Y. K.;
Kang, T. R.; Hu, Z. K.; Chen, Y. C. J. Am. Chem. Soc. 2008, 130, 2456e2457; (b)
Peterson, E. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2009, 48, 6328e6331; (c)
De, C. K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 17060e17061; (d)
Bui, T.; Syed, S.; Barbas, C. F. J. Am. Chem. Soc. 2009, 131, 8758e8759; (e) Uyeda,
C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228e9229; (f) Reisman, S. E.;
Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198e7199; (g) Ganesh,
M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464e16465.
1H), 2.06 (dt, J¼4.4, 13.0 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 24.3,
26.5, 40.2, 48.9, 51.8, 52.9, 53.0, 65.8, 77.2, 80.6, 115.5, 127.4, 127.5,
129.0, 138.9, 152.2, 165.2. HRMS (MALDI-TOF) calcd for
C
19H23NO5SNa
([MþNa]þ)
400.1189;
found
400.1186.
7. For selected carbene-catalyzed reactions, see: (a) Steward, K. M.; Corbett, M. T.;
Goodman, C. G.; Johnson, J. S. J. Am. Chem. Soc. 2012, 134, 20197e20206; (b)
Jacobsen, C. B.; Albrecht, L.; Udmark, J.; Jørgensen, K. A. Org. Lett. 2012, 14,
5526e5529; (c) Piel, I.; Stein-metz, M.; Hirano, K.; Frohlich, R.; Grimme, S.;
Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 4983e4987; (d) Suzuki, Y.; Md, A.;
Tanoi, T.; Nomura, N.; Sato, M. Tetrahedron 2011, 67, 4710e4715; (e) Ma-
hatthananchai, J.; Zheng, P. G.; Bode, J. W. Angew. Chem., Int. Ed. 2011, 50,
1673e1677; (f) Jousseaume, T.; Wurz, N. E.; Glorius, F. Angew. Chem., Int. Ed.
2011, 50, 1410e1414.
8. For selected phase-transfer-catalyzed reactions, see: (a) Lykke, L.; Halskov, K. S.;
Carlsen, B. D.; Chen, V. X.; Jørgensen, K. A. J. Am. Chem. Soc. 2013, 135,
4692e4695; (b) Liu, Y.; Shirakawa, S.; Maruoka, K. Org. Lett. 2013, 15,
1230e1233; (c) Mahe, O.; Dez, I.; Levacher, V.; Briere, J. F. Angew. Chem., Int. Ed.
2010, 49, 7072e7075; (d) He, R. J.; Ding, C. H.; Maruoka, K. Angew. Chem., Int. Ed.
2009, 48, 4559e4561; (e) He, R. J.; Wang, X. S.; Hashimoto, T.; Maruoka, K.
Angew. Chem., Int. Ed. 2008, 47, 9466e9468.
9. For recent reviews, see: (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877e1894; (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001,
171e196; (c) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701e1716; (d) Almasi, D.;
Alonso, D. A.; Ajera, C. N. Tetrahedron: Asymmetry 2007, 18, 299e365.
10. For several proline-catalyzed Michael additions, see: (a) List, B.; Pojarliev, P.;
Martin, H. J. Org. Lett. 2001, 3, 2423e2425; (b) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 4441e4444; (c)
Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737e3740; (d) Hanessian, S.;
Pham, V. Org. Lett. 2000, 2, 2975e2978; (e) Enders, D.; Seki, A. Synlett 2002,
26e28; (f) Chiand, Y. G.; Gellman, S. H. Org. Lett. 2005, 7, 4253e4256; (g) Moss’
e, S.; Alexakis, A. Org. Lett. 2005, 7, 4361e4364; (h) Mitchell, C. E. T.; Cobb, A. J.
A.; Ley, S. V. Synlett 2005, 611e614.
11. For examples of proline-derived organocatalysts, see: (a) Alexakis, A.; Andrey,
O. Org. Lett. 2002, 4, 3611e3614; (b) Mase, N.; Thayumanavan, R.; Tanaka, F.;
Barbas, C. F., III. Org. Lett. 2004, 6, 2527e2530; (c) Ishii, T.; Fujioka, S.; Sekiguchi,
Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558e9559; (d) Betancort, J. M.;
Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Synthesis 2004,
1509e1521; (e) Andrey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli, G. Adv.
Synth. Catal. 2004, 346, 1147e1168; (f) Cobb, A. J. A.; Longbottom, D. A.; Shaw,
D. M.; Ley, S. V. Chem. Commun. 2004, 1808e1809; (g) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84e96; (h)
Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369e1371; (i) Mase,
N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem.
Soc. 2006, 128, 4966e4967; (j) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett.
2006, 8, 2901e2904; (k) Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L. Org. Lett.
2006, 8, 6135e6138; (l) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem.
dEur. J. 2006, 12, 4321e4332; (m) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc.
2006, 128, 9624e9625; (n) Vishnumaya; Singh, V. K. Org. Lett. 2007, 9,
1117e1119; (o) Ni, B.; Zhang, Q.; Headley, A. D. Tetrahedron: Asymmetry 2007, 18,
1443e1447; (p) Xu, D.-Q.; Wang, L.-P.; Luo, S.-P.; Wang, Y.-F.; Zhang, S.; Xu, Z.-Y.
Eur. J. Org. Chem. 2008, 1049e1053; (q) Ni, B.-K.; Zhang, Q.-Y.; Dhungana, K.;
Headley, A. D. Org. Lett. 2009, 11, 1037e1040; (r) Chang, C.; Li, S.-H.; Reddy, R. J.;
Chen, K. Adv. Synth. Catal. 2009, 351, 1273e1278; (s) Reddy, R. J.; Kuan, H.-H.;
Chou, T.-Y.; Chen, K. Chem.dEur. J. 2009, 15, 9294e9298; (t) Wiesner, M.;
Neuberger, M.; Wennemers, H. Chem.dEur. J. 2009, 15, 10103e10109; (u) Zhu,
S.-L.; Yu, S.-Y.; Ma, D.-W. Angew. Chem., Int. Ed. 2008, 47, 545e548; (v) Xu, D.-Z.;
Shi, S.-S.; Liu, Y.-J.; Wang, Y.-M. Tetrahedron 2009, 65, 9344e9349; (w) Saha, S.;
Seth, S.; Moorthy, J. N. Tetrahedron Lett. 2010, 51, 5281e5286; (x) Cao, X.-Y.;
Zheng, J.-C.; Lia, Y.-X.; Shua, Z.-C.; Sun, X.-L.; Wang, B.-Q.; Tang, Y. Tetrahedron
2010, 66, 9703e9720; (y) Agarwal, J.; Peddinti, R. K. Tetrahedron Lett. 2011, 52,
117e121; (z) Lu, D.-F.; Gong, Y.-F.; Wang, W.-Z. Adv. Synth. Catal. 2010, 352,
644e650; (aa) Yoshida, M.; Sato, A.; Hara, S. Org. Biomol. Chem. 2010, 8,
3031e3036.
4.4.2.4. (4aS,5R,8aR,11aS,11bR)-10-Methyl-5-phenylhexahydro-
1H-pyrrolo[3,4-d]thiopyrano[40,30:2,3]pyrrolo[1,2-b]isoxazole-
24
9,11(2H,8aH)-dione (19a). White solid. [
a
]
D
ꢁ56.4 (c 0.33, CHCl3).
IR (KBr, nmax): 2923, 2853, 1707, 1435, 1382, 1287, 1135 cmꢁ1
.
1H
NMR (400 MHz, CDCl3): 7.36e7.30 (m, 4H), 7.26e7.21 (m, 1H),
d
4.92 (d, J¼7.2 Hz, 1H), 3.88 (dt, J¼4.5, 10.4 Hz, 1H), 3.76 (dd, J¼10.0,
15.8 Hz, 1H), 3.61 (dd, J¼10.0, 15.6 Hz, 1H), 3.53 (d, J¼7.2 Hz, 1H),
3.06 (s, 3H), 3.05 (dt, J¼4.5, 9.4 Hz, 1H), 2.98 (dd, J¼4.0, 14.6 Hz, 1H),
2.61e2.56 (m, 1H), 2.51 (td, J¼2.4, 7.2 Hz, 1H), 2.33 (td, J¼3.2,
10.4 Hz,1H), 1.84e1.79 (m,1H),1.69 (dt, J¼3.6,13.0 Hz,1H). 13C NMR
(100 MHz, CDCl3): d 24.9, 25.4, 25.9, 28.3, 47.0, 51.2, 53.8, 60.4, 75.7,
77.1, 126.9, 128.2, 128.8, 142.6, 173.6, 175.2. HRMS (MALDI-TOF, m/z)
calcd for C18H20N2O3SNa ([MþNa]þ) 367.1087; found 367.1071.
4.4.2.5. (4aS,5R,8aS,11aR,11bR)-10-Methyl-5-phenylhexahydro-
1H-pyrrolo[3,4-d]thiopyrano[40,30:2,3]pyrrolo[1,2-b]isoxazole-
28
9,11(2H,8aH)-dione (19b). Colorless oil. [
a
]
D
ꢁ161.9 (c 1.1, CHCl3).
IR (neat, nmax): 2923, 2853, 1708, 1434, 1280, 1138, 1008 cmꢁ1
.
1H
NMR (400 MHz, CDCl3): 7.34e7.30 (m, 2H), 7.27e7.21 (m, 3H),
d
4.97 (d, J¼8.0 Hz, 1H), 3.91 (dt, J¼7.2, 10.0 Hz, 1H), 3.72 (dd, J¼9.6,
15.2 Hz, 1H), 3.55 (d, J¼8.0 Hz, 1H), 3.43 (dd, J¼7.2, 15.0 Hz, 1H), 3.10
(dt, J¼2.0, 13.0 Hz, 1H), 3.04e2.99 (m, 4H), 2.64 (dd, J¼4.8, 8.8 Hz,
1H), 2.30e2.26 (m, 1H), 2.09e2.03 (m, 1H), 1.89 (dt, J¼3.2, 12.6 Hz).
13C NMR (100 MHz, CDCl3):
d 24.3, 25.2, 26.0, 33.6, 47.5, 48.9, 59.4,
59.6, 75.7, 77.0, 127.0, 128.2, 129.0, 142.0, 172.2, 173.0. HRMS
(MALDI-TOF, m/z) calcd for C18H20N2O3SNa ([MþNa]þ) 367.1087;
found 367.1082.
Acknowledgements
Grants from MOST (2010CB833200, 2013AA092903), NSFC grant
(21032002), and National Science Fund for Talent Training in Basic
Science (J1103310) are greatly appreciated. The authors also would
like to thank Dr. Yin Ding at Chemistry Department for her assis-
tance in the MALDI-TOF mass spectra analysis.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.116.
References and notes
12. For examples of other chiral amine-catalyzed Michael additions, see: (a) Paras,
N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370e4371; (b) Halland,
N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331e8338; (c) Okino,
T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672e12673; (d)
Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42,
1. Several recent reviews: (a) Aleman, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42,
774e793; (b) Chauhan, P.; Chimni, S. S. Beilstein J. Org. Chem. 2012, 8,
2132e2141; (c) Palomo, C.; Oiarbide, M.; Lopez, R. Chem. Soc. Rev. 2009, 38,
632e653; (d) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638e4660;
(e) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037e2046.
Please cite this article in press as: Mo, L.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.116

L. Mo et al. / Tetrahedron xxx (2013) 1e9
9
4955e4957; (e) Melchiorreand, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68,
4151e4157; (f) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126,
9906e9907; (g) Tsogeva, S. B.; Wei, S.-W. Chem. Commun. 2006, 1451e1453; (h)
Wei, S.-W.; Yalalov, D. A.; Tsogoeva, S. B.; Schmata, S. Catal. Today 2007, 121,
151e157; (i) Huang, H.-B.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128,
7170e7171; (j) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem.
, Int. Ed. 2006, 45, 3093e3097; (k) Kokotosand, C. G.; Kokotos, G. Adv. Synth.
Catal. 2009, 351, 1355e1362; (l) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2006, 128, 9413e9419; (m) Jiang, X.-X.; Zhang, Y.-F.; Chan, A. S. C.;
Wang, R. Org. Lett. 2009, 11, 153e156; (n) Hayashi, Y.; Gotoh, H.; Hayasi, T.;
Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212e4215; (o) Palomo, C.; Vera, S.;
Mielgoand, A.; Gomez-Bengoa, E. Angew. Chem., Int. Ed. 2006, 45, 5984e5987;
(p) Lombardo, M.; Chiarucci, M.; Quintavalla, A.; Trombini, C. Adv. Synth. Catal.
2009, 351, 2801e2806; (q) Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-
A. Org. Lett. 2007, 9, 923e925; (r) Lu, A.; Gao, P.; Wu, Y.; Wang, Y.; Zhou, Z.;
Tang, C.-C. Org. Biomol. Chem. 2009, 7, 3141e3147; (s) Freund, M.; Schenker, S.;
Tsogoeva, S. B. Org. Biomol. Chem. 2009, 7, 4279e4284; (t) Ting, Y.-F.; Chang, C.;
Reddy, R. J.; Magar, D. R.; Chen, K. Chem.dEur. J. 2010, 16, 7030e7038; (u) Yu, F.;
Jin, Z.-C.; Huang, H.-C.; Ye, T.-T.; Liang, X.-M.; Ye, J.-X. Org. Biomol. Chem. 2010, 8,
4767e4774; (v) Husmann, R.; Jorres, M.; Raabe, G.; Bolm, C. Chem.dEur. J. 2010,
16, 12549e12552; (w) Flock, A. M.; Krebs, A.; Bolm, C. Synlett 2010, 1219e1222;
(x) Nugent, T. C.; Shoaib, M.; Shoaib, A. Org. Biomol. Chem. 2011, 9, 52e56; (y)
Ding, X.-H.; Li, X.; Liu, D.; Cui, W.-C.; Ju, X.; Wang, S.-z.; Yao, Z.-J. Tetrahedron
2012, 68, 6240e6248; (z) Ding, X.-H.; Cui, W.-C.; Li, X.; Ju, X.; Liu, D.; Wang, S.-
z.; Yao, Z.-J. Tetrahedron Lett. 2013, 54, 1956e1959.
13. Song, X.-N.; Yao, Z.-J. Tetrahedron 2010, 66, 2589e2593.
14. Pierce, M. D.; Johnston, R. C.; Mahapatra, S.; Yang, H.; Carter, R. G.; Cheong, P.
H.-Y. J. Am. Chem. Soc. 2012, 134, 13624e13631.
15. For reviews on nitrone chemistry, see: (a) Huisgen, R. Angew. Chem., Int. Ed.
Engl. 1963, 2, 565e598; (b) Smith, L. I. Chem. Rev. 1938, 38, 193e285; (c) Hamer,
J.; Macaluso, A. Chem. Rev. 1964, 64, 473e495; (d) Yang, J. Synlett 2012,
2293e2297.
Please cite this article in press as: Mo, L.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.116