Diastereo- and enantioselective synthesis of densely functionalized cyclohexanones via double Michael addition of curcumins with nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2012.04.011

The asymmetric double Michael additions of curcumins to nitroalkenes to afford highly functionalized cyclohexanones have been carried out for the first time. A combination of a dihydrocinchonine-thiourea organocatalyst and K ₂CO₃ was found to be the most effective in obtaining the desired cyclohexanones in good yield, diastereoselectivity and enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2012.04.011

Tetrahedron: Asymmetry 23 (2012) 605–610
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereo- and enantioselective synthesis of densely functionalized
cyclohexanones via double Michael addition of curcumins with nitroalkenes
⇑
Narasimham Ayyagari, Irishi N.N. Namboothiri
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric double Michael additions of curcumins to nitroalkenes to afford highly functionalized
cyclohexanones have been carried out for the first time. A combination of a dihydrocinchonine-thiourea
organocatalyst and K2CO3 was found to be the most effective in obtaining the desired cyclohexanones in
good yield, diastereoselectivity and enantioselectivity.
Received 21 March 2012
Accepted 17 April 2012
Available online 19 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
also emerged as a fascinating area of research.14 In particular,
cascade [5+1] and [4+2] two-component double Michael reactions
Curcumin is an active ingredient in turmeric which is widely
used as a dietary spice and as a traditional medicine for the treat-
ment of diabetes, jaundice, rheumatoid arthritis, and so on, in east-
ern countries.1 In recent decades, studies on the biological activities
of curcumin such as anti-oxidant,2 anti-cancer,3 anti-inflamma-
tory,4 anti-metastatic,5 anti-HIV protease,6 and anti-Alzheimer’s7
have received considerable attention. Recently, the metal com-
plexes of the b-dicarbonyl moiety of the curcumins were also
shown to exhibit numerous biological activities.8 However, the
poor solubility and bioavailability of curcumin prevented it from
being used as a potent therapeutic agent. Therefore, the synthesis
of analogs and derivatives of curcumin, which possess superior sol-
ubility and bioavailability is a challenge for organic and medicinal
chemists. In this context, several cyclohexanone and heterocyclic
curcumin analogs were synthesized and shown to exhibit a range
of biological activities.9
under asymmetric organocatalyzed conditions have been exploited
to construct cyclohexanone scaffolds in excellent yields and
selectivities.15,16 However, the application of curcumin as a donor
and acceptor in such transformations has received attention only
recently.10,11,13
2. Results and discussion
In recent years, chiral bifunctional catalysts, containing a ter-
tiary amine and a thiourea moiety, set the standard for asymmetric
Michael additions of 1,3-dicarbonyl compounds to electron defi-
cient alkenes. This is due to the exceptional ability of the catalyst
to simultaneously activate both the substrates by aligning them
in the proper orientation such that the reaction takes place in a
highly stereoselective manner.17 Therefore, we envisioned that
the tertiary amine moiety in the quinuclidine ring would generate
the enolate of curcumin by deprotonating the active methylene,
whereas the thiourea moiety would activate the nitroalkene and/
or stabilize the nitronate through multiple hydrogen bonding with
the nitro group (Fig. 1).18 The chiral backbone would provide en-
ough rigidity to allow a double Michael addition to take place in a
highly stereoselective manner to afford 4-nitrocyclohexanones.
The synthesis of many biologically active compounds, such as
neuramidase inhibitors, and natural products, such as (ꢀ)-aphanor-
phine alkaloids, (ꢀ)-epibatidine, and the antitumor antibiotic (ꢀ)-
calcheamicinone, has been reported using 4-nitrocyclohexanone
as the key starting compound.19
Recently, we reported a highly diastereoselective synthesis of
functionalized cyclohexanones and dihydrofurans via cascade
double Michael and Michael–Feist–Benary reactions involving cur-
cumins and nitroalkenes. (Scheme 1).10,11 Subsequently, Ye et al.
reported the addition of curcumins to nitroalkenes catalyzed by
novel thiourea catalysts and isolated the single Michael adducts
in good yields and enantioselectivities.12 Very recently, Yan et al.
exploited the multiple nucleophilic and electrophilic sites of
curcumin in a domino Michael–Michael–oxa-Michael reaction of
curcumins and isatylidene malononitriles for the synthesis of spi-
13
rooxindoles.
Following the rationale outlined in Figure 1,18 we prepared var-
ious cinchona alkaloid derived thiourea catalysts A–E by reported
procedures (Fig. 2).20 We chose curcumin 1a and nitroalkene 2a
as the model substrates for the optimization of the reaction
conditions (Table 1). Initially, quinine-thiourea catalyst A,
dihydroquinine-thiourea catalysts B–C (30 mol %), and the
The synthesis of complex molecules, including natural products,
containing multiple stereogenic centers via asymmetric domino/
cascade reactions, often employing chiral organocatalysts, has
⇑
Corresponding author.
E-mail address: irishi@iitb.ac.in (I.N.N. Namboothiri).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.011

606
N. Ayyagari, I. N. N. Namboothiri / Tetrahedron: Asymmetry 23 (2012) 605–610
O
O
Ar
O
R
O
O
Ar
Ar
Ar
K2CO3, THF·H2O
1
+
Ar
OR
O
X = H, double Michael
addition
Ar
NO2
NO2
X
R
R
or
NO2
X = Br, Michael addition-
O-alkylation
2
3
4
X
Scheme. 1.
the reaction was carried out in two steps as follows: the crude reac-
tion mixture, after 3 days, was filtered through a short pad of silica
gel to remove the unreacted nitroalkene 1a and the resultant fil-
trate containing both the single and double Michael adducts was
concentrated; the residue was treated with K2CO3 in THF/H2O
(7.5:1).21 This led to the formation of the desired double Michael
adduct 3a in moderate yield and selectivity when THF was used
as the solvent in the first step (entry 11); good yield (75%), and
excellent diastereo- and enantioselectivity (dr 91:9 and ee 85%)
were achieved when dichloromethane was used as solvent (Table 1,
entry 12). A considerable decrease in the yield and a marginal de-
crease in the enantioselectivity were observed when the catalyst
loading was reduced to 20 mol % (Table 1, entry 13).
The optimized conditions, that is, 30 mol % of catalyst D in
CH2Cl2 followed by 0.8 equiv of K2CO3 in THF/H2O (7.5:1), were
employed for the reaction of curcumin 1a with various nitroal-
kenes 2a–m (Table 2). Nitroalkenes 2a–e with a variety of electron
donating substituents reacted with curcumin 1a to afford the dou-
ble Michael adducts 3a–e in good yields (70–75%) and diastereose-
lectivities (80:20–91:9, Table 2, entries 1–5). However, no clear
trend was observed in the enantioselectivities because nitroalkene
2c with three methoxy groups on the aromatic ring and 2e with a
weakly activating Me group gave lower selectivities, 62% and 63%,
respectively (entries 3 and 5), while other nitroalkenes 2a, 2b, and
2d with 1–2 alkoxy groups afforded the double Michael adducts
with better ee’s (83–91%, Table 2, entries 1, 2 and 4). Parent nitro-
styrene 2f and nitroalkenes 2g–2i with weakly deactivating
aromatic substituents afforded the products in 60–73% yield,
77:23–88:12 de, and 72–86% ee (Table 2, entries 6–9). Finally,
nitroalkenes 2j–2k with a strong electron withdrawing nitro group
and heteroaromatic nitroalkenes 2l–2m gave the products in high
yields (75–88%) and varying diastereoselectivities (50:50–90:10,
Table 2, entries 10–13). While the ee was high with o-nitro-nitro-
styrene 2j (entry 10), moderate to good ee’s were observed for the
other nitroalkenes 2k–m (Table 2, entries 11–13).
Chiral
scaffold
R22HN
S
N
H
N
R
H
O
O
O
H
Ar
N
O
R
1
2
Ar
Figure 1. Proposed transition state model for the double Michael addition of
curcumin 1 with nitroalkene 2.
dihydrocinchonine-thiourea catalyst D were screened in THF as the
solvent. This afforded the double Michael adduct 3a in low to mod-
erate yield and moderate to good selectivity (Table 1, entries 1–4). A
slight improvement in selectivity was observed when dihydro-
cinchonine-thiourea catalyst D was used in chloroform (Table 1,
entry 5). This prompted us to screen catalyst D in other solvents,
such as dichloromethane, dichloroethane, and a mixture of solvents
such as toluene–chloroform (1:1, Table 1, entries 6–8). Although
the selectivity was high in dichloromethane, the yield remained be-
low 50% (Table 1, entry 6). There was no reaction in the presence of
proline-thiourea catalyst E in dichloromethane (Table 1, entry 9).
The consistently low yield of the double Michael adduct 3a encoun-
tered in the above reactions was due to incomplete conversion of
the intermediate single Michael adduct, which was attributable to
the poor nucleophilicity of the nitronate arising from the initial Mi-
chael addition. We felt that a stronger base would be necessary for
the satisfactory completion of the second intramolecular Michael
addition step. To this end, NaOAc was used as an additive to catalyst
D in chloroform (Table 1, entry 10). Although this improved the
yield and the diastereoselectivity, the enantioselectivity decreased
dramatically (Table 1, entry 10). Finally, in order to ensure the com-
plete conversion of curcumin 1a into the double Michael adduct 3a,
Having demonstrated the scope of nitroalkenes 2 in our asym-
metric double Michael addition, we proceeded to explore the scope
of curcumins 1 by reacting a representative nitroalkene 2a with
CF3
CF3
CF3
NO2
CF3
CF3
CF3
NH
NH
NH
NH
CF3
NH
S
CF3
NH
NH
S
NH
S
NH
N
S
S
NH
N
N
N
N
N
N
N
MeO
NH
MeO
MeO
A
B
C
D
E
Figure 2. Catalysts screened for the double Michael addition of curcumin 1a and nitroalkenes 2a.

N. Ayyagari, I. N. N. Namboothiri / Tetrahedron: Asymmetry 23 (2012) 605–610
607
Table 1
Optimization of the enantioselective double Michael addition of curcumin 1a to nitroalkene 2a in the presence of thiourea catalysts A–E
O
O
O
O
Catalyst (30 mol%)
solvent, 3 days
1a
2a
MeO
OMe
NO2
MeO
NO2
MeO
OMe
MeO
3a
O
O
MeO
OMe
NO2
MeO
5a
Entry
Catalyst
Solvent
% Yielda
drb
eec
1
2
3
4
5
6
7
8
9
10
11
12
13
A
B
C
THF
THF
THF
THF
33
35
40
30
45
40
38
47
80:18
89:11
77:23
90:10
85:15
94:06
79:21
67:33
—
90:10
87:13
91:09
91:09
(+)ꢀ70
(+)ꢀ53
(+)ꢀ79
(ꢀ)ꢀ84
(ꢀ)ꢀ85
(ꢀ)ꢀ85
(ꢀ)ꢀ35
(ꢀ)ꢀ50
—
(ꢀ)ꢀ39
(ꢀ)ꢀ63
(ꢀ)ꢀ85
(ꢀ)ꢀ83
D
D
D
D
D
E
D
D
D
D
CHCl3
CH2Cl2
CH2Cl–CH2Cl
Toluene–CHCl3 (1:1)
CH2Cl2
d
—
e
CHCl3
64
55
75
63
THFf
f
CH2Cl2
CH2Cl2
f,g
a
b
c
d
e
f
Isolated yield after silica gel column chromatography.
Determined by 1H NMR.
Determined by chiral HPLC.
No reaction.
20 mol % NaOAc was used as an additive.
After 3 days, the crude reaction mixture was treated with 0.8 equiv K2CO3 in THF/H2O solvent system.
20 mol % of catalyst was used.
g
selected curcumins 1b, 1f, and 1l (Table 3). In these cases, the
yields, and the diastereo- and enantioselectivities were moderate.
4.2. General procedure for the asymmetric double Michael
addition of curcumin 1 to nitroalkenes 2
A solution of curcumin 1 (0.12 mmol, 1.0 equiv), nitroalkene 2
(0.18 mmol, 1.5 equiv), and catalyst (22 mg, 0.036 mmol,
3. Conclusion
D
30 mol %) in dichloromethane (0.5 mL) was stirred at room temper-
ature until curcumin 1 was completely consumed (monitored by
TLC). The solvent was evaporated under reduced pressure and the
excess nitroalkene 2 was removed by flash column chromatography
using EtOAc–pet ether (5–50%, gradient elution)as eluentto obtain a
mixture of 3 or 6 and the single Michael adduct. To this mixture in
THF (1.5 mL) and H2O (0.2 mL) was added K2CO3 (0.8 equiv,
14 mg) and the reaction mixture was stirred until the single Michael
adduct was completely consumed. The solvent was evaporated
under reduced pressure and the residue was purified by silica gel
column chromatography by eluting with EtOAc–pet ether (10–25%).
The asymmetric double Michael addition of curcumins to nitro-
alkenes has been carried out for the first time. The products, 4-nitro-
cyclohexanones, were formed in most cases in good to high yields,
excellent diastereoselectivities, and moderate to high enantioselec-
tivities in the presence of a dihydrocinchonine-thiourea organocat-
alyst in conjunction with an achiral base, such as K2CO3. Our future
work will include investigations of the synthetic and biological
applications of these highly functionalized cyclohexanones.
4. Experimental
4.1. General
4.3. 3,5-Bis(4-methoxyphenyl)-2-((E)-3-(4-methoxyphenyl)
acryloyl)-4-nitrocyclohexanone 3a10
The melting points recorded are uncorrected. NMR spectra (1H,
1H decoupled 13C) were recorded with TMS as the internal stan-
dard. The coupling constants (J values) are given in Hz. High reso-
lution mass spectra were recorded at 60–70 eV under ESI Q-TOF
conditions. Diastereoselectivities were determined by 1H NMR
and enantioselectivities by HPLC equipped with a PDA detector
and chiral column. Specific rotations were measured for solutions
of samples of known concentrations in CHCl3 using a polarimeter
equipped with a sodium vapor lamp. Nitroalkenes and curcumins
were prepared following literature protocols.22
½
a 1D8
ꢁ
¼ ꢀ41:0 (c 1.0, CHCl3); HPLC: Chiralcel AD–H (pet ether/
i-PrOH = 90/10, flow rate 1.0 mL/min, k = 370 nm), tR (major) =
19.0 min, tR (minor) = 23.8 min; 85% ee.
4.4. 3-(3,4-Dimethoxyphenyl)-5-(4-methoxyphenyl)-2-((E)-3-(4-
methoxyphenyl)acryloyl)-4-nitro-cyclohexanone 3b10
½
a 1D9
ꢁ
¼ ꢀ49:9 (c 1.0, CHCl3); HPLC: Chiralpak IA (pet ether/
i-PrOH = 80/20, flow rate 0.5 mL/min, k = 370 nm), tR (major) =
28.3 min, tR (minor) = 33.8 min; 83% ee.

608
N. Ayyagari, I. N. N. Namboothiri / Tetrahedron: Asymmetry 23 (2012) 605–610
Table 2
Enantioselective double Michael addition of curcumin 1a to nitroalkenes 2 in the presence of dihydrocinchonine-thiourea catalyst D and K2CO3
O
O
O
O
R
i) Catalyst D (30 mol%)
1a
2
CH2Cl2, RT, 3 - 4 days
MeO
OMe
ii) K2CO3 (0.8 equiv)
THF:H2O
MeO
NO2
R
NO2
OMe
3
O
R
O
Catalyst D (30 mol%)
K2CO3
THF:H2O
CH2Cl2, RT, 3 - 4 d
MeO
OMe
5
NO2
Entry
R
3
% Yielda
drb
eec
1
2
3
4
5
6
7
8
9
10
11
12
13
4-MeO-C6H4
3,4-(MeO)2-C6H3
3,4,5-(MeO)3-C6H3
Benzo[d][1,3]dioxole
4-Me-C6H4
C6H5
4-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
75
70
70
70
75
73
71
60
62
80
75
85
88
91:09
86:14
80:20
89:11
88:12
88:12
83:17
87:13
77:23
81:19
50:50
85:15
90:10
85
83
62
91
62
80
75
86
72
89
78
78
69
2-NO2-C6H4
3-NO2-C6H4
2-Furyl
3j
3k
3l
2-Thienyl
3m
a
b
c
Isolated yield after silica gel column chromatography.
Determined by 1H NMR.
Determined by chiral HPLC.
Table 3
Enantioselective double Michael addition of curcumins 1 to nitroalkene 2a in the presence of dihydrocinchonine-thiourea catalyst D and K2CO3
O
O
O
O
R
R
i) Catalyst D (30 mol%)
CH2Cl2, RT
3 - 4 days
1
R
R
ii) K2CO3 (0.8 equiv)
THF:H2O
NO2
NO2
MeO
6
2a
MeO
Entry
R
6
Yielda (%)
drb
eec
1
2
3
3,4-(MeO)2-C6H3
C6H5
2-Furyl
6b
6f
6l
58
70:30
69:31
80:20
34
44
60
55d
37e
a
b
c
Isolated yield after silica gel column chromatography.
Determined by 1H NMR.
Determined by chiral HPLC.
11 mg (20% yield) of single Michael adduct was isolated.
13 mg (22% yield) of single Michael adduct was isolated.
d
e
4.5. 5-(4-Methoxyphenyl)-2-((E)-3-(4-methoxyphenyl)acryloyl)-
4-nitro-3-(3,4,5-tri-methoxyphenyl)cyclohexanone 3c
3H), 3.80 (s, 3H), 3.85 (s, 3H), 3.87 (s, 6H), 4.66 (d, J = 2.2 Hz, 1H),
5.04 (t, J = 2.2 Hz, 1H), 6.41 (d, J = 15.3 Hz, 1H), 6.56 (s, 2H), 6.82 (d,
J = 8.6 Hz, 4H), 7.00 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.67
(d, J = 15.3 Hz, 1H), 17.47 (s, 1H); 13C NMR (100 MHz, CDCl3) d
33.4, 36.1, 45.3, 55.4, 55.5, 56.6, 61.0, 92.3, 104.3, 105.3, 114.4,
114.5, 117.4, 127.5, 128.4, 129.4, 130.3, 137.4, 137.8, 143.5, 154.1,
159.3, 161.9, 186.0, 187.6; MS (ES+) m/z (rel intensity) 578
([M+3]+, 12), 577 ([M+2]+, 38), 576 ([M+1]+, 100); HRMS (ES+) calcd
Yellow crystalline solid: Yield 49 mg (70%); mp 200–202 °C; IR
(KBr, cmꢀ1) 3437 (br, w), 2936 (w), 2835 (w), 1621 (w), 1592 (m),
1548 (m), 1513 (s), 1423 (m), 1256 (m), 1128 (m), 1032 (m); 1H
NMR (400 MHz, CDCl3) d 2.87 (dd, J = 18.8, 6.5 Hz, 1H), 3.30 (dd,
J = 18.8, 11.8 Hz, 1H), 3.47 (ddd, J = 11.8, 6.5, 2.2 Hz, 1H), 3.76 (s,

N. Ayyagari, I. N. N. Namboothiri / Tetrahedron: Asymmetry 23 (2012) 605–610
609
for C32H34NO9 (MH+) 576.2234, found 576.2218; ½a 1D9
ꢁ
¼ ꢀ47:6 (c 1.0,
4.11. 3-(3-Bromophenyl)-5-(4-methoxyphenyl)-2-((E)-3-(4-
methoxyphenyl)acryloyl)-4-nitrocyclohexanone 3i
CHCl3); HPLC: Chiralcel AD–H (pet ether/i-PrOH = 90/10, flow rate
1.0 mL/min, k = 370 nm), tR (major) = 22.2 min, tR (minor) = 27.2 -
min; 62% ee.
Yellow solid: Yield 43 mg (62%); mp 158–160 °C; IR (KBr,
cmꢀ1) 3435 (br, s), 2923 (w), 2841 (w), 1624 (m), 1602 (s),
1547 (s), 1512 (s), 1424 (w), 1254 (m), 1172 (m), 1032 (m),
829 (m); 1H NMR (400 MHz, CDCl3) d 2.89 (dd, J = 18.5, 6.2 Hz,
1H), 3.32 (dd, J = 18.5, 11.7 Hz, 1H), 3.39 (ddd, J = 11.7, 6.2,
2.3 Hz, 1H), 3.76 (s, 3H), 3.80 (s, 3H), 4.72 (d, J = 2.3 Hz, 1H),
5.00 (t, J = 2.3 Hz, 1H), 6.34 (d, J = 15.3 Hz, 1H), 6.82 (d,
J = 8.7 Hz, 2H), 6.84 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 7.9 Hz, 2H),
7.27 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.34–7.36 (m,
1H), 7.48 (d, J = 7.5 Hz, 1H), 7.56 (s, 1H), 7.68 (d, J = 15.3 Hz,
1H), 17.50 (s, 1H); 13C NMR (100 MHz, CDCl3) d 33.6, 35.9,
44.7, 55.4, 55.6, 91.9, 103.8, 114.5, 114.6, 117.0, 123.8, 127.0,
127.4, 128.4, 129.2, 130.4, 131.2, 131.3, 131.6, 143.9, 144.2,
159.4, 162.0, 185.5, 188.0; MS (ES+) m/z (rel intensity) 567
([M+4]+, 6), 566 ([M+3]+, 22), 565 ([M+2]+, 8), 564 (MH+, 21);
HRMS (ES+) C29H27NO6Br (MH+) 564.1022, found 564.1037;
4.6. 3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-methoxyphenyl)-2-((E)-3-
(4-methoxyphenyl)acryloyl)-4-nitrocyclohexanone 3d10
½
a 1D8
ꢁ
¼ ꢀ91:2 (c 1.0, CHCl3); HPLC: Chiralcel OD–H (pet ether/
i-PrOH = 85/15, flow rate 1.0 mL/min, k = 370 nm), tR (ma-
jor) = 36.3 min, tR (minor) = 31.0 min; 91% ee.
4.7. 5-(4-Methoxyphenyl)-2-((E)-3-(4-methoxyphenyl)acryloyl)-
4-nitro-3-(p-tolyl)-cyclohexanone 3e
Yellow crystalline solid: Yield 46 mg (75%); mp 135–137 °C; IR
(KBr, cmꢀ1) 3423 (br, w), 2956 (w), 2934 (w), 2841 (w), 1624 (w),
1601 (m), 1549 (s), 1513 (s), 1425 (m), 1256 (s), 1172 (s), 1032 (m),
830 (m); 1H NMR (400 MHz, CDCl3) d 2.36 (s, 3H), 2.85 (dd, J = 18.4,
6.2 Hz, 1H), 3.33 (dd, J = 18.4, 12.1 Hz, 1H), 3.43 (ddd, J = 12.1, 6.2,
2.0 Hz, 1H), 3.80 (s, 3H), 3.81 (s, 3H), 4.70 (d, J = 2.0 Hz, 1H), 5.00 (t,
J = 2.0 Hz, 1H), 6.40 (d, J = 15.3 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 6.84
(d, J = 7.5 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 7.19–7.29 (m, 6H), 7.66 (d,
J = 15.3 Hz, 1H), 17.46 (s, 1H); 13C NMR (100 MHz, CDCl3) d 21.3,
33.5, 35.6, 45.0, 55.4, 55.5, 92.4, 104.4, 114.5, 117.4, 127.6, 128.1,
128.4, 129.7, 130.3, 130.4, 138.1, 138.6, 143.3, 159.3, 161.8, 185.4,
188.1; MS (ES+) m/z (rel intensity) 502 ([M+3]+, 7), 501 ([M+2]+,
35), 500 (MH+, 100); HRMS (ES+) calcd for C30H30NO6 (MH+)
½
a 1D9
ꢁ
¼ ꢀ79:4 (c 1.0, CHCl3); HPLC: Chiralpak IC (pet ether/
i-PrOH = 80/20, flow rate 0.5 mL/min, k = 370 nm), tR (major) =
36.2 min, tR (minor) = 42.5 min; 71% ee.
4.12. 5-(4-Methoxyphenyl)-2-((E)-3-(4-methoxyphenyl)acryloyl)-
4-nitro-3-(2-nitrophenyl)cyclohexanone 3j10
½
a 1D9
ꢁ
¼ þ5:4 (c 1.0, CHCl3); HPLC: Chiralcel AD–H (pet ether/i-
PrOH = 80/20, flow rate 1.0 mL/min, k = 370 nm), tR (major) = 43.0
500.2073, found 500.2071; ½a D21
¼ ꢀ50:7 (c 1.0, CHCl3); HPLC: Chiral-
ꢁ
min, tR (minor) = 24.4 min; 89% ee.
cel OD–H (pet ether/i-PrOH = 80/20, flow rate 0.5 mL/min,
k = 370 nm), tR (major) = 32.4 min, tR (minor) = 26.6 min; 62% ee.
4.13. 5-(4-Methoxyphenyl)-2-((E)-3-(4-methoxyphenyl)acryloyl)-
4-nitro-3-(3-nitrophenyl)cyclohexanone 3k10
4.8. 5-(4-Methoxyphenyl)-2-((E)-3-(4-methoxyphenyl)acryoloyl)-
4-nitro-3-phenylcyclohexanone 3f10
½
a 1D9
ꢁ
¼ ꢀ18:6 (c 1.0, CHCl3); HPLC: Chiralcel AD–H (pet ether/i-
a 2D1
ꢁ
¼ ꢀ55:3 (c 1.0, CHCl3); HPLC: Chiralpak IA (pet ether/i-
PrOH = 95/05, flow rate 1.0 mL/min, k = 370 nm), tR (major) =
½
51.8 min, tR (minor) = 57.1 min; 79% ee.
PrOH = 90/10, flow rate 0.5 mL/min, k = 370 nm), tR (major) = 29.3 -
min, tR (minor) = 23.6 min; 79% ee.
4.14. 3-(Furan-2-yl)-5-(4-methoxyphenyl)-2-((E)-3-(4-metho-
xyphenyl)acryloyl)-4-nitrocyclohexanone 3l10
4.9. 3-(4-Chlorophenyl)-5-(4-methoxyphenyl)-2-((E)-3-(4-metho-
xyphenyl)acryloyl)-4-nitrocyclohexanone 3g10
½
a 1D9
ꢁ
¼ ꢀ71:5 (c 1.0, CHCl3); HPLC: Chiralcel OD–H (pet ether/i-
½
a 2D1
ꢁ
¼ ꢀ104:2 (c 1.0, CHCl3); HPLC: Chiralcel OD–H (pet ether/i-
PrOH = 80/20, flow rate 0.5 mL/min, k = 370 nm), tR (major) =
41.1 min, tR (minor) = 36.2 min; 78% ee.
PrOH = 80/20, flow rate 0.5 mL/min, k = 370 nm), tR (major) = 53.8 -
min, tR (minor) = 42.0 min; 75% ee.
4.15. 5-(4-Methoxyphenyl)-2-((E)-3-(4-methoxyphenyl)acryloyl)-
4-nitro-3-(thiophen-2-yl)cyclohexanone 3m10
4.10. 3-(4-Bromophenyl)-5-(4-methoxyphenyl)-2-((E)-3-(4-me-
thoxyphenyl)acryloyl)-4-nitrocyclohexanone 3h
½
a 1D8
ꢁ
¼ ꢀ77:4 (c 1.0, CHCl3); HPLC: Chiralcel OD–H (pet ether/i-
Yellow solid: Yield 42 mg (60%); mp 165–167 °C; IR (KBr, cmꢀ1
)
PrOH = 80/20, flow rate 0.5 mL/min, k = 370 nm), tR (major) =
3402 (br, m), 2929 (w), 1621 (m), 1602 (m), 1547 (m), 1512 (s),
1255 (vs), 1172 (s), 1031 (m), 827 (s), 738 (m); 1H NMR
(400 MHz, CDCl3) d 2.86 (dd, J = 17.3, 5.0 Hz, 1H), 3.29–3.41 (m,
2H), 3.76 (s, 3H), 3.81 (s, 3H), 4.72 (d, J = 2.2 Hz, 1H), 4.97 (t,
J = 2.2 Hz, 1H), 6.34 (d, J = 15.3 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H),
6.84 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.6 Hz,
2H), 7.30 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.69 (d,
J = 15.3 Hz, 1H), 17.51 (s, 1H); 13C NMR (100 MHz, CDCl3) d 33.5,
35.7, 44.6, 55.4, 55.5, 92.0, 103.8, 114.5, 114.6, 116.9, 122.4,
127.4, 128.4, 129.2, 130.0, 130.3, 132.8, 140.8, 143.9, 159.4,
162.0, 185.3, 188.1; MS (ES+) m/z (rel intensity) 567 ([M+4]+, 30),
566 ([M+3]+, 93), 565 ([M+2]+, 28), 564 (MH+, 100); HRMS (ES+)
51.2 min, tR (minor) = 33.9 min; 69% ee.
4.16. 5-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)-2-((E)-3-
(3,4-dimethoxyphenyl)acryloyl)-4-nitrocyclohexanone 6b10
½
a 2D5
ꢁ
¼ ꢀ44:3 (c 1.0, CHCl3); HPLC: Chiralcel AD–Helen (pet
ether/i-PrOH = 80/20, flow rate 0.5 mL/min, k = 370 nm), tR (ma-
jor) = 42.1 min, tR (minor) = 47.8 min; 34% ee.
4.17. 3-(4-Methoxyphenyl)-4-nitro-5-phenyl-2-((E)-3-phenyl-
acryloyl)cyclohexanone 6f10
calcd for
C
29H27NO6Br (MH+) 564.1022, found 564.1029;
a 2D1
ꢁ
¼ ꢀ112:3 (c 1.0, CHCl3); HPLC: Chiralcel OD–H (pet ether/i-
½
a 2D5
ꢁ
¼ ꢀ40:3 (c 1.0, CHCl3); HPLC: Chiralcel AD–H (pet ether/i-
½
PrOH = 85/15, flow rate 0.5 mL/min, k = 370 nm), tR (major) =
PrOH = 80/10, flow rate 0.5 mL/min, k = 370 nm), tR (major) =
14.0 min, tR (minor) = 21.1 min; 44% ee.
69.5 min, tR (minor) = 54.8 min; 86% ee.

610
N. Ayyagari, I. N. N. Namboothiri / Tetrahedron: Asymmetry 23 (2012) 605–610
Asymmetric Organocatalysis; VCH: Weinheim, Germany, 2004; (h) Grondal, C.;
Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167; (i) Matthias, R. M.; Grondal, C.;
Enders, D. Angew. Chem., Int. Ed. 2007, 46, 1570.
4.18. 5-(Furan-2-yl)-2-((E)-3-(furan-2-yl)-acryloyl)-3-(4-methoxy-
phenyl)-4-nitrocyclohexanone 6l10
15. [5+1] type reactions: (a) Kohler, E. P.; Dewey, C. S. J. Am. Chem. Soc. 1924, 46,
1267; (b) Silvanus, A. C.; Groombridge, B. J.; Andrews, B. I.; Kociok-Köhn, G.;
Carbery, D. R. J. Org. Chem. 2010, 75, 7491; (c) Zhang, D.; Xu, X.; Tan, J.; Liu, Q.
Synlett 2010, 917; (d) Fusco, C. D.; Lattanzi, A. Eur. J. Org. Chem. 2011, 3728; (e)
Li, X.; Wang, B.; Zhang, J.; Yan, M. Org. Lett. 2011, 13, 374; (f) Wu, B.; Liu, G. G.;
Li, M. Q.; Zhang, Y.; Zhang, S. Y.; Qiu, J. R.; Xu, X. P.; Ji, S. J.; Wang, X. W. Chem.
Commun. 2011, 47, 3992; (g) Wang, L. L.; Peng, L.; Bai, J. F.; Jia, L. N.; Luo, X. Y.;
Huang, Q. C.; Xu, X. Y.; Wang, L. X. Chem. Commun. 2011, 47, 5593.
½
a 2D5
ꢁ
¼ ꢀ26:6 (c 0.2, CHCl3); HPLC: Chiralcel OD–H (pet ether/i-
PrOH = 80/20, flow rate 0.5 mL/min, k = 370 nm), tR (major) =
18.9 min, tR (minor) = 25.3 min; 60% ee.
Acknowledgments
16. [4+2] type reactions: (a) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett.
2004, 45, 9185; (b) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto, Y.
Tetrahedron Lett. 2006, 62, 365; (c) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.;
Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 3732; (d) Li, H.; Zu, L.; Xie,
H.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9, 1833; (e) Tan, B.; Shi, Z.;
Chua, J.; Zhong, G. Org. Lett. 2008, 10, 3425; (f) Wu, L.-Y.; Bencivenni, G.;
Mancinelli, M.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed.
2009, 48, 7196; (g) Ma, A.; Ma, D. Org. Lett. 2010, 12, 3634; (h) He, P.; Liu, X.;
Shi, J.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 936; (i) Rajkumar, S.; Shankland, K.;
Brown, G. D.; Cobb, A. J. A. Chem. Sci. 2012, 3, 584.
17. For asymmetric organocatalytic conjugate additions: (a) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701; (b) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron:
Asymmetry 2007, 18, 299; For cinchona alkaloids in metal free asymmetric
synthesis: (c) Yeboah, E. M. O.; Yeboah, S. O.; Singh, G. S. Tetrahedron 2011, 67,
1725; For thiourea catalyzed asymmetric reactions: (d) Connon, S. J. Chem.
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I.N.N.N. thanks DST India for financial assistance. N.A. thanks
UGC India for a senior research fellowship. The authors thank SAIF,
IIT Bombay for selected NMR data.
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