Highly enantioselective Michael addition of ketones to nitroolefins catalyzed by (S)-pyrrolidine arenesulfonamide

Article abstract of DOI:10.1016/j.tetasy.2007.05.037

A new type of catalyst for the asymmetric Michael addition reaction has been designed and synthesized. This catalyst, (S)-pyrrolidine arenesulfonamide 1, resulted in high yields (up to 93%), excellent diastereoselectivities (syn/anti ratio up to 99/1), an

Full text of DOI:10.1016/j.tetasy.2007.05.037

Tetrahedron: Asymmetry 18 (2007) 1443–1447
Highly enantioselective Michael addition of ketones to nitroolefins
catalyzed by (S)-pyrrolidine arenesulfonamide
Bukuo Ni, Qianying Zhang and Allan D. Headley*
Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA
Received 3 May 2007; accepted 24 May 2007
Abstract—A new type of catalyst for the asymmetric Michael addition reaction has been designed and synthesized. This catalyst, (S)-
pyrrolidine arenesulfonamide 1, resulted in high yields (up to 93%), excellent diastereoselectivities (syn/anti ratio up to 99/1), and excel-
lent enantioselectivities (ee up to 99%) for various cyclic ketones and nitroolefins.
ꢀ
2007 Elsevier Ltd. All rights reserved.
1
. Introduction
group, was used as a Michael acceptor. Although the cata-
lysts developed to date exhibit a relatively high reactivity
and selectivity, the development of new catalysts that are
capable of improving diastereo- and enantioselectivity for
the asymmetric Michael reaction at room temperature is
still warranted.
The organocatalytic asymmetric Michael addition reaction
has emerged as one of the most powerful and efficient
methods for C–C bond formation in synthetic organic
chemistry. Several highly efficient chiral organocatalysts
have been designed and synthesized for this reaction. Pro-
1
2
line and its pyrrolidine-type chiral amine derivatives are
among the organocatalysts that have been found to be
2
. Results and discussion
3
highly successful for asymmetric organic transformations.
3
a
3b
3c
The pioneering works by Hanessian, List, and Enders
It has been proposed that the asymmetric Michael reaction
catalyzed by proline proceeds via an enamine intermediate,
and that both the secondary amine of the pyrrolidine ring
and the carboxylic acid functionalities are required for the
catalytic activity. Herein, we have designed a new type of
proline-derived catalyst, (S)-pyrrolidine arenesulfonamide
serve to demonstrate that L-proline is a very effective cata-
lyst for asymmetric Michael addition reactions, the key
step for these reactions being the formation of an enamine
intermediate. Owing to the poor solubility of proline in
many organic solvents, numerous novel proline derivatives,
4
5
such as pyrrolidine-pyridine, aminomethylpyrrolidine,
1
, which has proven to be an effective organocatalyst for
0
6
7
2
,2 -bipyrrolidine, pyrrolidinelterazole, (S)-(+)-2-pyrrol-
idinemethanol, pyrrolidine-thiourea, and pyrrolidine-
based chiral ionic liquids which have improved solubility,
have been developed and used as excellent organocatalysts
in asymmetric Michael addition reactions.
reactions where proline derivatives are normally used. The
two electron-withdrawing trifluoromethyl groups on the
phenyl ring, combined with sulfonyl group are expected to
effectively increase the acidity of the sulfonamide hydrogen
and as a result, facilitate required proton transfer. Catalyst
8
9
1
0
1
can be easily prepared from the commercially available
Recently, Wang et al.11 described the synthesis of (S)-pyr-
rolidine trifluoromethanesulfonamide and hydrophobic
polyfluorous pyrrolidine sulfonamide that effectively cata-
lyzes diastereo- and enantioselective Michael addition reac-
tions of ketones and aldehydes with nitroolefins. However,
a relatively low enantioselectivity was obtained when nitro-
styrene, which contained an election-withdrawing CF3
N-Boc-(S)-2-aminomethylpyrrolidine and 3,5-bis(trifluoro-
methyl)benzenesulfonyl chloride, as shown in Scheme 1.
Herein, we report the results of the studies using 1 as cata-
lyst to promote highly diastereo- and enantioselective Mi-
chael addition reactions of ketones with nitroolefins.
Initially, the Michael reaction of cyclohexanone and nitro-
styrene in various solvents was examined at room tem-
perature using (S)-pyrrolidine arenesulfonamide 1 as the
*
Corresponding author. E-mail: allan_headley@tamu-commerce.edu
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.037

1444
B. Ni et al. / Tetrahedron: Asymmetry 18 (2007) 1443–1447
CF3
CF3
NH2
1. Et
N, CH Cl
3 2 2
H O
N
ClO2S
N
Boc
+
2
. CF CO H
3
2
S
CF3
N
H
CH Cl
2 2
CF
3
O
1
Scheme 1. Synthesis of (S)-pyrrolidine arenesulfonamide.
catalyst, the results are summarized in Table 1. Both
Table 2. Asymmetric Michael reaction of cycloketones to nitroolefins
CH CN and THF gave high diastereoselectivities, but
yields were low (8–10%) (Table 1, entries 1 and 2). Dichlo-
3
O
O
Ar
Ar
catalyst 1 (15%)
i-PrOH, 4 d, r.t.
NO2
romethane and an ionic liquid [BMIM]BF were also poor
4
+
NO2
solvents in terms of product yields (Table 1, entries 4 and
X
X
5
). DMSO, i-PrOH, and DMF were superior solvents
a
b
c
and showed good yields, high enantioselectivities, and dia-
stereoselectivities (Table 1, entries 6–8). Based on these re-
sults, i-PrOH was chosen as the solvent to study the
effectiveness of catalyst 1. The Michael addition reaction
proceeded smoothly at room temperature to give the de-
sired adduct 2a in 83% yield with high enantioselectivity
Entry Product
Ph
Yield (%) ee (%) dr (syn/anti)
O
O
O
O
O
O
O
O
O
NO2
1
83
77
94
99
98/2
96/4
2
a
C6H5-4-Me
NO2
(
94% ee) and diastereoselectivity (syn/anti = 98/2).
2
2
b
Table 1. Solvent effect for asymmetric Michael addition reaction of
cyclohexanone and trans-b-nitrostyrene
C6H5-4-OMe
NO2
3
4
5
6
7
8
65
87
83
91
93
92
99
95
94
93
96
95
99/1
99/1
94/6
99/1
98/2
99/1
O
O
Ph
2c
Ph
catalyst 1 (15%)
NO2
C6H5-2-CF3
NO2
+
solvent, 4 d, r.t.
NO2
2a
2
d
a
b
d
Entry
Solvent
CH CN
THF
DCM
Neat
[BMIM]BF
DMSO
i-PrOH
DMF
Yield (%)
ee (%)
dr (syn/anti)
C6H5-4-Br
NO2
c
c
c
c
c
1
2
3
4
5
6
7
8
3
10
8
<5
8
96/4
93/7
c
2
e
c
c
C6H5-2-NO2
NO2
4
5
61
83
85
83
94
92
95/5
98/2
92/8
2
f
C H -2,4-Cl
6
4
2
a
b
c
NO2
Yield of isolated product.
Determined by chiral HPLC analysis (Chiralpak AS-H).
Not determined.
2g
d
1
C6H4-2-Cl
NO2
Determined by H NMR spectroscopy (400 MHz).
2
h
Having established the standard reaction conditions for the
Michael addition of cyclohexanone with trans-b-nitrostyr-
ene, we next investigated the scope of the Michael reaction
for which catalyst 1 is effective with a series of ketones and
nitroolefins in i-PrOH as the solvent; the results were
shown in Table 2. From these results, it is obvious that
all cyclic ketones efficiently undergo Michael reactions with
different aryl-substituted nitroolefins in the presence of
Ph
NO2
NO2
9
92
90
92
93
98/2
91/9
2i
S
O
Ph
10
2
j
O
1
5 mol % of catalyst 1 in i-PrOH at room temperature to
a
b
c
Isolated yield.
give the Michael adducts 2a–i in high yields with excellent
enantio- (92–99% ee) and diastereoselectivities (syn/anti
ratio up to 99/1). The results in Table 1 also show that
the nature of the substituents on aryl groups slightly influ-
ences the yields and enatioselectivities. For nitroolefins
with electron-rich groups (methyl and methoxy), the reac-
tion proceeded smoothly to afford Michael adduct 2b,c in
Determined by Chiral HPLC.
Determined by H NMR.
1
nearly enantiomerically pure form (99% ee) and with excel-
lent diastereoselectivities, although the isolated yields were

B. Ni et al. / Tetrahedron: Asymmetry 18 (2007) 1443–1447
1445
relatively low (65–77%) (Table 2, entries 2 and 3). For
4.2. The data for the Michael addition reaction
nitroolefins with electron-withdrawing groups, the Michael
adducts 2d–h were obtained in high yields (83–93%) with
excellent enantio- (93–96% ee) and diastereoselectivities
4
4.2.1. (S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone 2a.
Typical procedure: Catalyst 1 (11 mg, 15 mol %) was
dissolved in i-PrOH (1 mL) and cyclohexanone (59 mg,
0.6 mmol) and b-nitrostyrene (30 mg, 0.2 mmol) was
added. The reaction mixture stirred at room tempera-
ture for 4 days. The reaction mixture was concentrated in
vacuum and the residue was purified by flash silica gel col-
umn (eluent: hexane/ethyl acetate = 4/1) to give the Mi-
(
syn/anti ratio up to 99/1) (Table 2, entries 4–7). Moreover,
tetrahydrothiopyran-4-one and tetrahydro-4H-pyran-4-
one were also suitable substrates as Michael donors (Table
2
, entries 8 and 9). Compared to the results obtained by
1
1b
Wang et al.
in which (S)-pyrrolidine trifluoromethane-
sulfonamide was used as the catalyst, the (S)-pyrrolidine
arenesulfonamide 1 is superior in enantioselectivity for
1
chael adduct 2a (41 mg, 83%) as a white solid. H NMR
(400 MHz, CDCl ) d 7.35–7.23 (m, 3H), 7.20–7.14 (m,
1
2
nitroolefins bearing electron-deficient aryl groups.
3
2H), 4.94 (dd, J = 12.4 and 4.4 Hz, 1H), 6.43 (dd,
J = 12.4 and 10.0 Hz, 1H), 3.76 (dt, J = 9.6 and 4.4 Hz,
1
1
H), 2.74–2.64 (m, 1H), 2.52–2.34 (m, 2H), 2.13–2.03 (m,
H), 1.83–1.50 (m, 4H), 1.30–1.18 (m, 1H); C NMR
3. Conclusion
13
(
7
0
100 MHz, CDCl ) d 211.9, 137.7, 128.9, 128.2, 127.8,
3
20
In conclusion, a new catalyst, (S)-pyrrolidine arenesulfon-
amide 1, was prepared and successfully applied to the asym-
metric Michael addition reaction of cyclic ketones with
nitroolefins. The reactions proceeded smoothly at room
temperature to give high yields (up to 93%), excellent dia-
stereoselectivities (syn/anti ratio up to 99/1), and excellent
enantioselectivities (ee up to 99%). The design of improved
catalysts and their application to other types of reactions
are currently being investigated in our laboratory.
8.9, 52.5, 43.9, 42.7, 33.2, 28.5, 25.0; ½aꢀ ¼ ꢁ23:2 (c
D
.15, CH Cl ); syn/anti = 98/2; ee = 94%; HPLC (Chir-
2
2
alpak AS-H, i-propanol/hexane = 10/90, flow rate
0
3
.7 mL/min, k = 238 nm): tminor = 22.7 min, tmajor =
5.2 min.
4.2.2. (S)-2-((R)-1-(4-Methylphenyl)-2-nitroethyl)cyclohexa-
none 2b.
J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 4.91 (dd,
J = 12.4 and 4.8 Hz, 1H), 4.62 (dd, J = 12.4 and 10.0 Hz,
1
1b
1
H NMR (400 MHz, CDCl ) d 7.12 (d,
3
1H), 3.72 (dt, J = 10.0 and 4.8 Hz, 1H), 2.71–2.62 (m,
4. Experimental
1H), 2.51–2.32 (m, 2H), 2.31 (s, 3H), 2.12–2.02 (m, 1H),
1
3
1.82–1.50 (m, 4H), 1.30–1.18 (m, 1H);
C NMR
4.1. (S)-2-[(2,6-Trifluoromethanebenzenesulfonyl)amino-
methyl]pyrrolidine 1
(100 MHz, CDCl ) d 212.0, 137.4, 134.6, 129.6, 128.0,
3
20
79.0, 52.6, 43.6, 42.7, 33.2, 28.5, 25.0, 21.0; ½aꢀ ¼ ꢁ17:9
D
(
c 0.36, CH Cl ); syn/anti = 96/4; ee = 99%; HPLC (Chir-
2 2
To a solution of N-Boc-(S)-2-aminomethylpyrrolidine
alpak AS-H, i-propanol/hexane = 10/90, flow rate 0.8 mL/
min, k = 254 nm): tminor = 15.4 min, tmajor = 25.9 min.
(
500 mg, 2.5 mmol) in CH Cl (15 mL) was added Et N
2 2 3
(
3
2
0.42 mL, 3.0 mmol). The solution was cooled to 0 ꢁC and
,5-bis(trifluoromethyl)benzenesulfonyl chloride (782 mg,
.5 mmol) was added. After the addition, the reaction mix-
4.2.3. (S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclo-
4
1
hexanone 2c.
H NMR (400 MHz, CDCl ) d 7.08 (d,
3
ture was brought to room temperature and stirred for 17 h,
diluted in CH Cl (60 mL) and washed with 1 M HCl
J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.95 (dd,
J = 12.4 and 4.4 Hz, 1H), 4.58 (dd, J = 12.4 and 10.0 Hz,
1H), 3.78 (s, 3H), 3.72 (dt, J = 10.0 and 4.4 Hz, 1H),
2.69–2.60 (m, 1H), 2.53–2.33 (m, 2H), 2.13–2.04 (m, 1H),
2
2
(
5 mL), saturated aqueous NaHCO (10 mL), and brine
3
(
15 mL). The organic phase was dried over Na SO and
2
4
1
3
concentrated to give the residue, which was used for the
next step without further purification.
1.82–1.50 (m, 4H), 1.30–1.17 (m, 1H);
C NMR
(100 MHz, CDCl ) d 212.0, 137.4, 134.6, 129.6, 128.0,
3
2
D
0
7
9.0, 52.6, 43.6, 42.7, 33.2, 28.5, 25.0, 21.0; ½aꢀ ¼ ꢁ11:8
The above compound was dissolved in a 1/1 mixture of tri-
fluoroacetic acid and dichloromethane (10 mL) and the
solution was stirred for 2 h at rt, at which time the solvent
was evaporated under reduced pressure. The pH was ad-
(c 0.31, CH Cl ); syn/anti = 99/1; ee = 99%. HPLC (Chir-
2 2
alpak AD, i-propanol/hexane = 10/90, flow rate 0.5 mL/
min, k = 254 nm): tminor = 25.5 min, tmajor = 31.8 min.
justed to 8 with aqueous NaHCO and the aqueous phase
4.2.4.
ethyl)cyclohexanone 2d.
(S)-2-((R)-1-(2-Trifluoromethanephenyl)-2-nitro-
1
3
1b
1
was extracted with CH Cl (3 · 20 mL). The organic phase
H NMR (400 MHz, CDCl3)
2
2
was dried over NaSO and the solvent was evaporated to
d 7.69 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.39
(dd, J = 16.4 and 10.0 Hz, 2H), 5.02 (dd, J = 12.0 and
6.8 Hz, 1H), 4.76 (dd, J = 12.0 and 4.0 Hz, 1H), 4.13–
4.05 (m, 1H), 3.06–2.96 (m, 1H), 2.54–2.40 (m, 3H),
2.18–2.08 (m, 1H), 1.84–1.52 (m, 4H), 1.38–1.24 (m, 1H);
4
give the residue, which was recrystallized from ethyl acetate
and hexane to give the pure title compound 1 (1.05 g, 88%
20
for two steps). Mp: 189–191 ꢁC; ½aꢀ ¼ ꢁ10 (c 0.30,
D
1
MeOH); H NMR (300 MHz, CD OD) d 8.44 (s, 2H),
3
1
3
8
2
.33 (s, 1H), 3.75–3.65 (m, 1H), 3.40–3.13 (m, 4H), 2.21–
.00 (m, 3H), 1.65–1.78 (m, 1H); C NMR (75 MHz,
C NMR (100 MHz, CDCl ) d 211.5, 137.1, 132.4,
3
1
3
128.0, 127.8, 126.6 (q, J = 20.8 Hz, 1C), 125.5, 122.7,
20
CD OD) d 144.3, 134.1 (q, J = 137.2 Hz, 2C), 128.7,
78.5, 52.5, 43.0, 39.1, 33.5, 28.7, 25.5; ½aꢀ ¼ ꢁ15:7 (c
3
D
ꢁ
1
1
25.5, 122.7; IR (neat) m = 1687, 1352, 1278, 1129 cm
;
0.64, CH Cl ); syn/anti = 99/1; ee = 95%; HPLC (Chir-
2
2
HRMS (ESI) m/z (%) calcd for C H F N O S:
alpak AD, i-propanol/hexane = 10/90, flow rate 0.5 mL/
min, k = 254 nm): tminor = 13.4 min, tmajor = 18.3 min.
1
3
15
6
2
2
3
77.0753, found: 377.0752.

1446
B. Ni et al. / Tetrahedron: Asymmetry 18 (2007) 1443–1447
4
none 2e.
.2.5. (S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)cyclohexa-
1
4.2.10. (R)-Tetrahydro-3-((R)-2-nitro-1-phenylethyl)pyran-
11b
0a
1
1
H NMR (400 MHz, CDCl ) d 7.45 (dd,
4-one 2j.
H NMR (400 MHz, CDCl ) d 7.37–7.26
3
3
J = 6.8 and 1.6 Hz, 2H), 7.06 (dd, J = 6.8 and 1.6 Hz,
H), 4.92 (dd, J = 12.4 and 4.4 Hz, 1H), 4.60 (dd,
J = 12.4 and 10.0 Hz, 1H), 3.74 (dt, J = 9.6 and 4.4 Hz,
(m, 3H), 7.21–7.16 (m, 2H), 4.96 (dd, J = 12.4 and 4.8 Hz,
1H), 4.64 (dd, J = 12.4 and 10.0 Hz, 1H), 4.20–4.10 (m,
1H), 3.87–3.68 (m, 2H), 3.70 (dd, J = 11.2 and 5.2 Hz,
1H), 3.27 (dd, J = 11.2 and 10.0 Hz, 1H), 2.93–2.83 (m,
2
1
1
H), 2.70–2.60 (m, 1H), 2.52–2.32 (m, 2H), 2.14–2.04 (m,
H), 1.84–1.52 (m, 4H), 1.30–1.18 (m, 1H); C NMR
1
3
13
1H), 2.73–2.61 (m, 1H), 2.60–2.53 (m, 1H); C NMR
(
7
0
100 MHz, CDCl ) d 211.4, 136.8, 132.1, 129.9, 121.7,
(100 MHz, CDCl ) d 207.3, 136.2, 129.2, 128.3, 127.9,
3
3
20
20
8.5, 52.3, 43.4, 42.7, 33.1, 28.4, 25.0; ½aꢀ ¼ ꢁ14:2 (c
78.7, 71.6, 69.0, 53.3, 42.9, 41.3; ½aꢀ ¼ ꢁ27:9 (c 0.45,
D
D
.40, CH Cl ); syn/anti = 94/6; ee = 94%; HPLC (Chir-
CH Cl ); syn/anti = 91/9; ee = 93%; HPLC (Chiralpak
2
2
2
2
alpak AS-H, i-propanol/hexane = 10/90, flow rate 1 mL/
min, k = 254 nm): tminor = 18.2 min, tmajor = 32.7 min.
AS-H, i-propanol/hexane = 50/50, flow rate 0.5 mL/min,
k = 254 nm): tminor = 20.7 min, tmajor = 25.8 min.
4
2
1
4
.2.6. (S)-2-((R)-2-Nitro-(2-nitrophenyl)ethyl)cyclohexanone
9
1
f.
H NMR (400 MHz, CDCl ) d 7.84 (d, J = 8.0 Hz,
3
Acknowledgement
H), 7.59 (t, J = 8.0 Hz, 1H), 7.48–7.42 (m, 2H), 4.98–
.87 (m, 2H), 4.32 (dt, J = 8.8 and 4.8 Hz, 1H), 2.99–2.91
We are grateful to the Robert A. Welch Foundation
T-1460) for financial support of this research.
(
(
m, 1H), 2.52–2.32 (m, 2H), 2.16–2.08 (m, 1H), 1.88–1.78
m, 2H), 1.72–1.40 (m, 4); C NMR (100 MHz, CDCl3)
(
1
3
d 211.0, 150.8, 133.1, 132.8, 129.3, 128.6, 124.9, 77.6,
2
D
0
5
2.2, 42.8, 38.7, 33.2, 28.3, 25.3; ½aꢀ ¼ ꢁ148:3 (c 0.65,
References
CH Cl ); syn/anti = 99/1; ee = 93%; HPLC (Chiralpak
2
2
AD, i-propanol/hexane = 5/95, flow rate 1 mL/min,
k = 238 nm): tminor = 32.3 min, tmajor = 48.0 min.
1
2
. Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992.
. For selected reviews regarding of organocatalysis, see: (a)
List, B. Acc. Chem. Res. 2004, 37, 548; (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) Notz,
W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
4
hexanone 2g.
.2.7. (S)-2-((R)-1-(2,4-Dichlorophenyl)-2-nitroethyl)cyclo-
9
1
H NMR (400 MHz, CDCl ) d 7.41 (d,
3
J = 2.0 Hz, 1H), 7.28–7.14 (m, 2H), 4.95–4.80 (m, 2H),
5
80; (d) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719;
4
2
1
1
2
.25 (dt, J = 9.6 and 4.8 Hz, 1H), 2.93–2.82 (m, 1H),
(
e) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975.
.52–2.32 (m, 2H), 2.16–2.07 (m, 1H), 1.87–1.50 (m, 4H),
1
3
3. (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975; (b) List,
B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423; (c)
Enders, D.; Seki, A. Synlett 2002, 26; (d) Chi, Y.; Gellman, S.
H. Org. Lett. 2005, 7, 4253; (e) Mosse, S.; Alexakis, A. Org.
Lett. 2005, 7, 4361; (f) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 84; (g) Mitchell, C. E. T.; Cobb, A. J. A.; Ley,
S. V. Synlett 2005, 611; (h) Mase, N.; Thayumanavan, R.;
Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527; (i)
Planas, L.; Perand-Viret, J.; Royer, J. Tetrahedron: Asym-
metry 2004, 15, 2399; (j) Cobb, A. J. A.; Longbottom, D. A.;
Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808; (k)
Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas,
C. F., III. Tetrahedron Lett. 2001, 42, 4441; (l) Betancort,
J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737.
.40–1.25 (m, 1H); C NMR (100 MHz, CDCl ) d 211.3,
3
35.2, 134.1, 130.1, 127.7, 51.6, 42.8, 40.6, 33.1, 28.4,
20
5.3; ½aꢀ ¼ ꢁ40:7 (c 0.71, CH Cl ); syn/anti = 98/2;
D
2
2
ee = 96%; HPLC (Chiralpak AS-H, i-propanol/hex-
ane = 5/95, flow rate 1 mL/min, k = 238 nm): tminor
=
1
6.0 min, tmajor = 29.9 min.
4
none 2h.
.2.8. (S)-2-((R)-1-(2-Chlorophenyl)-2-nitroethyl)cyclohexa-
1
0a
1
H NMR (400 MHz, CDCl ) d 7.37 (d,
3
J = 6.8 Hz, 2H), 7.30–7.28 (m, 3H), 4.90 (d, J = 2.0 Hz,
1
2
1
1
4
H), 4.89 (s, 1H), 4.35–4.25 (m, 1H), 2.98–2.86 (m, 1H),
.52–2.34 (m, 2H), 2.16–2.06 (m, 1H), 1.86–1.54 (m, 4H),
1
3
.40–1.24 (m, 1H); C NMR (100 MHz, CDCl ) d 211.6,
3
35.4, 134.5, 130.3, 129.4, 128.9, 127.3, 77.2, 51.7, 42.8,
4. Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem.
Soc. 2004, 126, 9558.
5
20
1.0, 33.0, 28.5, 25.2; ½aꢀ ¼ ꢁ49:2 (c 0.50, CHCl ); syn/
D
3
. (a) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F.,
III. Org. Lett. 2004, 6, 2527; (b) Betancort, J. M.; Sakthivel,
K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III.
Synthesis 2004, 1509.
anti = 99/1; ee = 95%; HPLC (Chiralpak AD, i-propanol/
hexane = 5/95, flow rate 1 mL/min, k = 254 nm): tminor
=
1
3.0 min, tmajor = 18.9 min.
6
. (a) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611; (b)
Andrey, O.; Vidonne, A.; Alexakis, A. Tetrahedron Lett.
2003, 44, 7901; (c) Andrey, O.; Alexakis, A.; Bernardinelli, G.
Org. Lett. 2003, 5, 2559; (d) Andrey, O.; Alexakis, A.;
Tomassini, A.; Bernardinelli, G. Adv. Synth. Catal. 2004, 346,
4
one 2i.
.2.9. (R)-Tetrahydro-3-((R)-2-nitro-1-phenylethyl)pyran-4-
H NMR (400 MHz, CDCl ) d 7.37–7.26 (m,
3
11b
1
3
1
1
1
1
H), 7.21–7.16 (m, 2H), 4.96 (dd, J = 12.4 and 4.8 Hz,
H), 4.64 (dd, J = 12.4 and 10.0 Hz, 1H), 4.20–4.10 (m,
H), 3.87–3.68 (m, 2H), 3.70 (dd, J = 11.2 and 5.2 Hz,
H), 3.27 (dd, J = 11.2 and 10.0 Hz, 1H), 2.93–2.83 (m,
1
147.
7
. (a) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V.
Chem. Commun. 2004, 1808; (b) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem.
1
3
H), 2.73–2.61 (m, 1H), 2.60–2.53 (m, 1H); C NMR
(
100 MHz, CDCl ) d 207.3, 136.2, 129.2, 128.3, 127.9,
3
2
005, 3, 84.
20
7
8.7, 71.6, 69.0, 53.3, 42.9, 41.3; ½aꢀ ¼ ꢁ17:7 (c 0.44,
D
8. Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L. Org. Lett.
CH Cl ); syn/anti = 98/2; ee = 92%; HPLC (Chiralpak
2
2
2006, 8, 6135.
AS-H, i-propanol/hexane = 40/60, flow rate 0.5 mL/min,
k = 254 nm): tminor = 22.3 min, tmajor = 29.0 min.
9. Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006,
8, 2901.

B. Ni et al. / Tetrahedron: Asymmetry 18 (2007) 1443–1447
1447
1
1
0. (a) Luo, S.-Z.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng,
J.-P. Angew. Chem., Int. Ed. 2006, 45, 3093; (b) Ni, B.; Zhang,
Q.; Headley, A. D. Green Chem. 2007, 9. doi:10.1039/
b702081c.
Wang, W. Chem. Eur. J. 2006, 12, 4321; (c) Zu, L.; Wang, J.;
Li, H.; Wang, W. Org. Lett. 2006, 8, 3077.
12. The (S)-pyrrolidine trifluoromethanesulfonamide (20 mol %)
catalyzed Michael addition of trans-b-nitro-2-(trifluoro-
methyl)styrene with cyclohexanone at 0 ꢁC resulted in 70%
yield and 88% ee (see Ref. 11b).
1. (a) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005,
4
4, 1369; (b) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.;