A highly regio- and enantioselective organocatalyzed Michael addition of malonates to nitrodienes

Article abstract of DOI:10.1016/j.tetasy.2014.02.007

An organocatalyzed direct Michael addition of unsubstituted/substituted malonates, acetoacetate, or acetylacetones to conjugated nitrodienes using a cinchona alkaloid-based thiourea catalyst is disclosed. The addition products were formed in high yields and regioselectivity. The enantioselectivities of the addition products were high in most cases and could significantly be improved upon by a single recrystallization. The addition products easily undergo chemoselective nitro group reduction and subsequent lactamization with a high synthetic potential.

Full text of DOI:10.1016/j.tetasy.2014.02.007

Tetrahedron: Asymmetry 25 (2014) 516–522
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Tetrahedron: Asymmetry
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A highly regio- and enantioselective organocatalyzed Michael
addition of malonates to nitrodienes
⇑
Raghunath Chowdhury, Ganga B. Vamisetti, Sunil K. Ghosh
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An organocatalyzed direct Michael addition of unsubstituted/substituted malonates, acetoacetate, or
acetylacetones to conjugated nitrodienes using a cinchona alkaloid-based thiourea catalyst is disclosed.
The addition products were formed in high yields and regioselectivity. The enantioselectivities of the
addition products were high in most cases and could significantly be improved upon by a single recrys-
tallization. The addition products easily undergo chemoselective nitro group reduction and subsequent
lactamization with a high synthetic potential.
Received 17 January 2014
Accepted 12 February 2014
Available online 20 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
introduction of nitrodienes7 as Michael acceptors since the
additional C@C can be exploited for further synthetic maneuvers.
The catalytic asymmetric Michael addition is the one to be the
most frequently used C–C and C–X (X = heteroatom) bond forming
reactions in organic synthesis.1 In recent years, the organocatalytic
version of this reaction has brought a renaissance in organic
synthesis.2 Amongst the organocatalyzed asymmetric Michael
reactions developed, use of electron-deficient, simple olefins as
Michael acceptors is well documented.2 In comparison, extended
conjugated systems such as activated dienes and enynes have
rarely been used as acceptors. Asymmetric conjugate additions to
such acceptors can provide intermediates with more functional
groups. This would enhance the utility of the approach in the
synthesis of natural products and pharmaceutical intermediates.
However, in addition to the enantioselectivity, the extra conjuga-
tion in the chosen acceptors adds an additional issue of regioselec-
tivity that is 1,4- versus 1,6-addition. The principle of vinilogy3
states that the electronic effect of directing functional groups can
Enamine catalysts have been used for the exclusive 1,4-addition
of carbonyl compounds to nitrodienes.8 Michael additions of 1,
3-dicarbonyl compounds to nitroolefins catalyzed by bifunctional
organocatalysts have been studied in detail.9 Until now, little pro-
gress has been made with the organocatalyzed Michael reactions
of 1,3-dicarbonyl compounds with nitrodiene acceptors. The only
reported examples available employ acyclic or cyclic b-ketoesters
as donors and bifunctional hydrogen bonding catalysts such as
chiral guanidines10 or 60-OH Cinchona alkaloids11 as promoters in
Michael additions to nitrodienes. Nitroenynes have recently been
used as substrates in metal-12 or organocatalyzed13 selective 1,
4-additions of malonates, b-keto esters, and b-diketones. However,
systematic studies on organocatalyzed 1,4-additions of malonates
to nitrodienes have not been reported.14,15 As part of our research
efforts toward the development of organocatalyzed reactions,16 we
herein report the development of an efficient, highly regio-, and
enantioselective protocol for the Michael addition of malonates,
b-ketoesters, and b-diketones to nitrodienes, promoted by some
Cinchona alkaloid-based thiourea catalysts.17 The utility of this
propagate through a conjugated
p-system. However, in practice,
1,4-additions4 are usually preferred over 1,6-addition5 with
common electron deficient dienes.
Nitroalkenes have been well studied as Michael acceptors2 in
the field of organocatalyzed reactions because of their high electro-
philicity, originating from the strong electron-withdrawing nature
and hydrogen bonding ability of the nitro group. Moreover, the
enantioenriched nitroalkane adducts are valuable synthons for
various chiral heterocyclic skeletons found in bioactive molecules.6
The synthetic utility can be significantly enhanced upon by the
strategy has been exemplified by synthesizing a chiral c-lactam,
expected to be an intermediate for natural products and
therapeutically useful agents.
2. Results and discussion
A number of initial experiments were performed to screen
different bifunctional thiourea derived organocatalysts 1,18 219
and 3–720 (Fig. 1) for the Michael addition of dimethyl malonate
8a to nitrodiene 9a (Table 1). These bifunctional thiourea catalysts
⇑
Corresponding author. Tel.: +91 2225595012; fax: +91 22 25505151.
E-mail address: ghsunil@barc.gov.in (S.K. Ghosh).
http://dx.doi.org/10.1016/j.tetasy.2014.02.007
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

R. Chowdhury et al. / Tetrahedron: Asymmetry 25 (2014) 516–522
517
activity under the above reaction conditions (Table 1, entries 3–7)
and the reactions were complete in all cases. Catalysts 5 and 7
showed the highest enantioselectivity (Table 1, entries 5 and 7).
The enantiopreference with catalysts 3–5 was opposite to that of
catalyst 7 and provided the adduct ent-10a.
S
S
S
ArN
H
N
H
N
H
NAr
H
H2N
N
H
NAr
H
2
1
In order to determine the influence of the solvent on the conju-
gate addition, other solvents were also screened using catalyst 7
(Table 1, entries 8–12) at the same temperature. Amongst the
chosen solvents, dichloromethane and the ethers (Et2O and THF)
R
R
NHAr
NH
X
N
S
CF3
N
N
N
H
Ar =
N
CF3
Table 2
X
S
NH2Ar
Michael addition of malonates 8a–c to nitrodienes 9a–ha
3: R = CH=CH2; X =H
R1
R2
6: R = CH=CH2; X = OMe
7: R = CH2CH3; X = OMe
4: R = CH=CH2; X = OMe
5: R = CH2CH3; X = OMe
NO2
Figure 1. Bifunctional organocatalysts 1–7 used herein.
9a: R1 = Ph, R2 = H
: R1 = 2-MeOC6H4, R2 = H
9b
9c: R1 = 4-NO2C6H4, R2 = H
Table 1
: R1 = 4-BrC6H4, R2 = H
9d
Optimization of the asymmetric Michael addition of dimethyl malonate 8a to
9e: R1 = 4-ClC6H4, R2 = H
9f: R1 = Ph, R2 = CH3
nitrodiene 9aa
: R1 = 3-BrC6H4, R2 = H
9g
Ph
Ph
Catalyst
MeO2C
MeO2C
(10 mol%)
+
R1
28 o
C
MeO2C
NO2
R1
R2
9h
:
R2
NO2
=
CO2Me
8a
7
catalyst
9a
(10 mol%)
toluene
RO2C
R3
NO2
10a
+
RO2C
CO2R
CO2R
Entry
Catalyst
Solvent
Time (h)
Yield (%)b [ee (%)]c
R3
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
7
7
7
7
7
7
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Et2O
THF
DMF
CH3CN
Toluene
48
30
44
24
26
42
24
47
24
48
72
72
72
n.r.d
10a: R1 = Ph, R2, R3 = H, R = Me
10b
55e [49]
72 [ꢁ42]
83 [ꢁ50]
82 [ꢁ70]
88 [38]
90 [70]
91 [68]
89 [62]
90 [65]
20e [25]
45e [54]
85 [88]f
: R1 = Ph, R2, R3 = H, R = Et
10c: R1 = 2-MeOC6H4, R2, R3 = H, R = Me
10d
8a: R = Me, R3 = H
: R = Et, R3 = H
8b
: R1 = 4-NO2C6H4, R2, R3 = H, R = Me
10e: R1 = 4-BrC6H4, R2, R3 = H, R = Me
8c: R = Me, R3 = allyl
: R1 = 4-ClC6H4, R2, R3 = H, R = Me
10f
10g: R1 = 4-ClC6H4, R2, R3 = H, R = Et
10h: R1 = Ph, R2 = Me, R3 = H, R = Me
: R1 = 3-BrC6H4, R2, R3 = H, R = Me
10i
9
10
11
12
13
10j R1
R2
:
R
3 = H, R = Me
=
a
Reactions were performed with dimethyl malonate 8a (0.5 mmol) and nitro-
10k: R1 = Ph, R2 = H, R3 = CH2CH=CH2, R = Me
diene 9a (0.25 mmol) in the presence of the respective catalysts (10 mol %) in dry
solvents (0.5 mL).
b
Yield of chromatographically homogeneous products.
Determined by HPLC analysis on a Daicel chiralpak AD-H column.
n.r. = no reaction.
Incomplete reaction.
Entry Nitrodiene Temp (°C)/Time (d) Product
Yieldb (%)
85 (47)d
eec (%)
c
1
9a
9a
9a
9b
9c
9d
9e
9f
ꢁ20/3
ꢁ20/3
ꢁ20/6
ꢁ20/6
28/1.5
0/1.7
0/2.5
0/2.5
ꢁ20/6
ꢁ20/3
28/2
10a
88 (99)e
88 (99)e
88
d
2
ent-10af 85 (48)d
e
3g
4
10b
10c
10d
10e
10f
10g
10h
10i
80
f
Reaction performed at ꢁ20 °C.
75h (50%)d 89 (99)e
5
6
70
87
93
76
84
85
7
are capable of playing multiple roles in a reaction. A portion of the
catalyst can nucleophilically activate the methylene/methyne
group of the Michael donor by proton abstraction, while H-bonding
from the thiourea part of the catalyst with the nitrodiene enhances
the electrophilicity of the latter. Moreover, it brings both reaction
partners into close proximity (open transition state to closed
transition state) for better regio- and enantiocontrol. In order to
optimize the reaction conditions, a number of experiments were
performed using 10 mol % each of the catalysts 1-7 in different
solvents and at different temperatures as presented in Table 1. In
toluene at room temperature (ꢀ28 °C), the trans-1,2-diaminocyclo-
hexane based bis-thiourea catalyst 1 failed to produce the desired
addition product 10a (Table 1, entry 1). The monothiourea catalyst
2 showed modest activity under the same conditions to furnish
10a in moderate yield and enantioselectivity (Table 1, entry 2).
The Cinchona alkaloid-derived catalysts 3–7 showed high catalytic
8g
9
91 (45%)d
66h
95
80 (99)e
80
9f
10
11
12i
9g
9h
9a
85
72
85
10j
76
0/6
10kj
45h
a
Unless otherwise specified, all of the reactions were performed with nitrodiene
(0.25 mmol) with malonate 8a (0.5 mmol) in the presence of 10 mol % of the cat-
alyst 7 in dry toluene (0.5 mL).
b
Yield of chromatograhically homogeneous product.
Determined by HPLC analysis using a chiral stationary phase.
Yield after single recrystallization.
Ee after a single recrystallization.
Catalyst 5 was used instead of catalyst 7.
Malonate 8b was used.
Incomplete reaction.
Malonate 8c was used.
c
d
e
f
g
h
i
j
20 mol % of catalyst 7 was used.

518
R. Chowdhury et al. / Tetrahedron: Asymmetry 25 (2014) 516–522
produced similar yields and enantioselectivities of product 10a as
obtained in toluene (Table 1, entries 8–10). The reaction rate in
Et2O was comparable to that in toluene. The yield and enantiose-
lectivity were low in polar aprotic solvents such as CH3CN and
DMF (Table 1, entries 11 and 12). This may be due to the loss of
H-bonding interactions between the catalyst and the nitrodiene.
When the addition reaction was performed using catalyst 7 at a
lower temperature (ꢁ20 °C) in toluene, the enantioselectivity of
the addition product 10a improved significantly (88% ee, Table 1,
entry 13), although the reaction took longer time to complete. Un-
der all these conditions, the reaction furnished regioselectively the
1,4-addition product only. Based on these results, we determined
the optimized reaction conditions to be: dimethyl malonate 8a
(2 equiv), nitrodiene 9a (1 equiv), catalyst 7 (10 mol %), with
toluene as the solvent at a reaction temperature of ꢁ20 °C.
with acceptable yield and enantioselectivity. However, the reaction
was sluggish and remained incomplete (80% conversion) presum-
ably due to unfavored interactions between the substrate and
nucleophile. The 4,4-dialkyl substituted nitrodiene 9h also under-
went the Michael addition with dimethyl malonate 8a at room tem-
perature. The corresponding addition product 10j was obtained in
good yield and with good enantioselectivity. The majority of the
addition products (Table 2, 10a–d and 10g) were obtained as solids
and a few of them after single recrystallization provided the prod-
ucts with improved enantiomeric excess (Table 2, entries 1, 2, 4,
and 8) of the products. The reaction of dimethyl allylmalonate 8c
with nitrodiene 9a was very slow at ꢁ20 °C. Although the reaction
rate was enhanced at 0 °C, the reaction remained incomplete (60%
conversion) even after 144 h.
The scope of this Michael addition was further explored by
using nitrodiene 9a and 1,3-dicarbonyl compounds 11a–c. Under
the optimized conditions using catalyst 7, nitrodiene 9a upon reac-
tion with acetylacetone 11a gave the addition product 12a (Table 3)
in excellent yield and with high enantioselectivity. The ee of 12a
was significantly improved (>96%) upon by a single recrystalliza-
tion. As with acetylacetone, methyl acetoacetate 11b was also
added to nitrodiene 9a to give adduct 12b in 90% yield as an insep-
arable 1/1 mixture of diastereoisomers. Each diastereoisomer was
also formed with high enantioselectivity as determined by HPLC.
Methyl 2-propargylacetoacetate 11c also underwent this organo-
catalyzed Michael addition to nitrodiene 9a to give adduct 12c as
an inseparable mixture of diastereoisomers in a ratio of 70/30.
The major diastereoisomer had moderate enantioselectivity while
the minor one showed high enantioselectivity.
Next, the scope of the optimized protocol was explored by using
different nitrodienes 9a–h and three Michael donors, dimethyl
malonate 8a, diethyl malonate 8b, and dimethyl allylmalonate 8c
(Table 2). In these cases, the 1,4-addition products 10a–k were
formed exclusively with good to excellent yields and enantioselec-
tivities. Substituents on the aromatic ring of the 4-aryl-1-nitrobut-
adienes had a minimal effect on the reactivity except for the
2-substituted aryl group where the reaction was slower, probably
due to steric factors. The solubility of nitrodienes 9c–e in toluene
at ꢁ20 °C was poor. Hence, these reactions were performed at
0 °C and/or at room temperature. Nitrodiene 9f bearing a 3-methyl
group also resulted in the formation of the addition product 10h
Table 3
Michael addition of 1,3-dicarbonyl compounds to nitrodiene 9aa
The absolute configuration of the Michael adduct 10b was as-
signed to be (S) by measuring the specific rotation value
Ph
O
O
7
catalyst
(10 mol%)
{½a 2D3
ꢂ
¼ ꢁ23:0 (c 1, CHCl3); lit.14
½
a 2D2
ꢂ
¼ þ26:1 (c 1.15, CHCl3) for
+
R
9a
H3C
toluene
NO2
H3COC
R'
the antipode of 10b with 95% ee}. The absolute configurations of
the other products 10a and 10c–g were tentatively assigned to
be (S) in analogy with 10b. The absolute configuration of the
Michael adduct ent-10a was assigned to be (R), since its rotation
was opposite to that of 10a.
-20 oC
R'
COR
11a: R = Me, R' = H
12a: R = Me, R' = H
12b
11b
: R = OMe, R' = H
11c: R = OMe, R' = 2-propynyl
: R = OMe, R' = H
12c
: R = OMe, R' = 2-propynyl
The stereochemical outcome for the formation of (S)-10a can be
explained by the dual activation model originally proposed by
Takemoto et al.9b and adopted by others12,13,21 as shown in the
transition state assembly depicted in Fig. 2. The NO2 group in 9a
can complex to the thiourea moiety of the catalyst 7 by two
H-bonding interactions, while the enol form of the dimethyl
malonate can form an H-bond to the bridgehead-N as shown in
TS-1 (Fig. 2). The most favored approach would be at the Si-face
of the nitrodiene 9a because this route would involve the least ste-
ric interaction at the transition state for the H-bonding interaction
of the enol form of dimethyl malonate 8a to the bridgehead-N lead-
ing to an (S)-configuration for product 10a. An alternative binding
model of substrates to catalyst as proposed by Papai22 can be
Entry
Nucleophile
Product
Yieldb (%)
drc
eed (%)
1
2
3
11a
11b
11c
12a
12b
12c
92
90
95
—
1/1
7/3
79 (96)e
83f, 81g
54f, 80g
a
Unless otherwise specified, all the reactions were performed with nitrodiene 9a
(0.25 mmol) with the nucleophile (0.5 mmol) in the presence of 10 mol % of the
catalyst 7 in dry toluene (0.5 mL) at ꢁ20 °C for 24 h.
b
Yield of chromatographically homogeneous product.
Determined from 1H NMR of the crude product.
Determined by HPLC analysis using a chiral stationary phase.
Improved by a single recrystallization,
c
d
e
f
Ee for the first or major diastereoisomer.
Ee for the second or minor diastereoisomer.
g
N
CF3
N
CF3
S
OMe
S
OMe
F3C
N
H
O
N
H
O
N
F3C
N
H
O
N
H
N
O
H
N
O
N
H
O
MeO
O
O
MeO
R
OMe
OMe
R
TS-1
TS-2
Figure 2. Transition state model.

R. Chowdhury et al. / Tetrahedron: Asymmetry 25 (2014) 516–522
519
invoked wherein the NO2 group in 9a can complex to the proton-
ated bridgehead-N as shown in TS-2 (Fig. 2), while the thiourea
moiety of catalyst 7 can participate in two H-bonding interactions
with the enolate form of dimethyl malonate. The most favored ap-
proach would be at the Re-face of the nitrodiene 9a because this
would involve the least steric interaction at the transition state
for the H-bonding interactions, leading again to an (S)-configura-
tion for product 10a.
DBU (8 lL, 0.05 mmol, 20 mol %) was added to the homogenous
reaction mixture and stirring was continued at room temperature
(ꢀ28 °C) until completion of the reaction. The resulting mixture
was diluted with EtOAc and washed with water. The organic phase
was dried over MgSO4 and evaporated under reduced pressure. The
residue was purified by column chromatography over silica gel
using hexane/EtOAc as eluent to give the desired addition products
rac-10a–k or rac-12a–c.
In order to show the utility of our method, the addition product
10a was transformed into
c
-lactam 13 (Scheme 1). The chemose-
4.3. General procedure 2. Asymmetric Michael addition of 1,3-
dicarbonyl compounds to nitrodienes
lective reduction of the nitro group in 10a using Zn and acetic acid
gave the intermediate amine, which upon cyclization furnished the
desired lactam 13 in very good yield. The trans-relative configura-
tion of lactam 13 was confirmed by 1H–1H ROESY spectra wherein
no nOe interactions were observed between H3 and H4 (Scheme 1).
1,3-Dicarbonyl compound 8a–c or 11a–c (0.5 mmol) was added
to a stirred solution of nitrodiene 9a–h (0.25 mmol) and thiourea
catalyst 7 (16 mg, 0.025 mmol, 10 mol %) in toluene (0.5 mL) at
ꢁ20 °C. The reaction mixture was stirred at the same temperature
for 14–144 h, diluted with EtOAc, and washed with water. The or-
ganic phase was dried over MgSO4 and evaporated under reduced
pressure. The residue was purified by column chromatography
over silica gel using hexane/EtOAc as eluent to give the desired
addition products 10a–k and 12a–c.
Ph
Ph
1. Zn, AcOH
H4
H
2. Aq. Na2CO3
MeO2C
NO2
MeO2C
85%
H3
CO2Me
10a
Scheme 1. Synthesis of a
N
4.4. (S)-Methyl-2-carbomethoxy-3-(nitromethyl)-5-phenyl-4-
pentenoate 10a
O
13
c
-lactam.
Following general procedure 2, product 10a was obtained as a
white solid. Yield: 65 mg (85%, 88% ee); Recrystallized from hex-
ane–EtOAc; Yield: 36 mg (47%); mp 94–95 °C (hexane–EtOAc);
½
a 2D4
ꢂ
¼ ꢁ24:2 (c 1.2, CHCl3) 99.5% ee; 1H NMR (200 MHz, CDCl3):
3. Conclusion
d = 7.26–7.33 (m, 5H), 6.57 (d, J = 15.8 Hz, 1H), 6.0–6.18 (m, 1H),
4.62–4.80 (m, 2H), 3.73–3.77 (m, 2H), 3.76 (s, 3H), 3.73 (s,
3H) ppm; 13C NMR (50 MHz, CDCl3): d = 167.6, 167.5,135.8, 135.5,
128.6 (2C), 128.2, 126.6 (2C), 123.3, 76.9, 53.3, 52.9, 52.8,
In conclusion, we have developed an asymmetric Michael addi-
tion of malonates and 1,3-dicarbonyl compounds to obtain various
substituted nitrodienes using easily accessible cinchona alkaloid-
based thiourea organocatalysts. The addition reactions were highly
regioselective providing 1,4-addition products exclusively with
good to excellent yields and enantioselectivities. The addition
products hold promise for the construction of stereo- and regio-
chemically diverse heterocyclic skeletons comprised of flexible
rings and containing embedded functionalities.
41.2 ppm; IR (KBr):
m = 2982, 2877, 2843, 1739, 1554, 1464, 1431,
1256, 1154, 742 cmꢁ1; elemental analysis calcd (%) for C15H17NO6:
C 58.63, H 5.58, N 4.56, found: C 58.97, H 5.63, N 4.53; the enantio-
meric excess of the recrystallized product was determined by HPLC
with a Daicel chiralpak AD-H column [k = 220 nm], eluent: 2-propa-
nol/hexane (10/90), flow rate = 0.8 mL/min, tminor = 21.13 min
(0.33%), tmajor = 25.85 min (99.67%).
4. Experimental
4.1. General
4.5. (R)-Methyl-2-carbomethoxy-3-(nitromethyl)-5-phenyl-4-
pentenoate ent-10a
Solvent removal was carried out using a rotary evaporator con-
nected to a dry ice condenser. TLC (0.5 mm) was carried out using
homemade silica plates with fluorescence indicator. Column chro-
matography was performed on silica gel (230-400 mesh). 1H and
13C NMR spectra were recorded on a 200 MHz (1H: 200 MHz, 13C:
50 MHz) spectrometer. 1H and 13C shifts are given in ppm, d scale
and are measured relative to internal CHCl3 and CDCl3 as stan-
dards, respectively. High resolution mass spectra were recorded
at 60–70 eV with a Q-TOF spectrometer (ESI, Ar). Enantiomeric ex-
cess (ee) determinations were carried out by HPLC using an instru-
ment fitted with a Daicel chiralpak AD-H/OD-H/AS-H column and
UV detector with k fixed at 220 nm. Nitrodienes 9a-h were pre-
pared following the general procedures reported in the litera-
ture.8c,23 Organocatalysts 1,18 2,19 and 3–720 were prepared by
following the literature.
Following general procedure 2 and using catalyst 5 instead of cat-
alyst 7, product ent-10a was obtained as a white solid. Yield: 65 mg
(85%, 88% ee); Recrystallized from hexane-EtOAc; Yield: 37 mg
(48%); mp 92–93 °C (hexane–EtOAc); ½a D24
¼ þ23:3 (c 1.2, CHCl3)
ꢂ
>98% ee. The enantiomeric excess of the recrystallized product
was determined by HPLC with a Daicel chiralpak AD-H column
[k = 220 nm], eluent: 2-propanol/hexane (10/90), flow rate = 0.8
mL/min, tmajor = 19.04 min (99.35%), tminor = 23.28 min (0.65%).
4.6. (S)-Ethyl-2-carboethoxy-3-(nitromethyl)-5-phenyl-4-pent-
enoate 10b
Yellow solid; Yield: 67 mg (80%, 88% ee); mp 48–49 °C, lit.14 mp
49 °C; ½a 2D5
ꢂ
¼ ꢁ23:0 (c 1.0, CHCl3); lit.14
½
a 2D2
ꢂ
¼ þ26:1 (c 1.15,
CHCl3) 95% ee; 1H NMR (200 MHz, CDCl3): d = 7.23–7.33 (m, 5H),
6.56 (d, J = 15.8 Hz, 1H), 6.10 (dd, J = 9.0, 15.8 Hz, 1H), 4.62–4.80
(m, 2H), 4.13–4.27 (q, J = 7.2 Hz, 4H), 3.62–3.80 (m, 2H), 1.19 (q,
J = 7.2 Hz, 6H) ppm; 13C NMR (50 MHz, CDCl3): d = 167.3, 167.1,
135.8, 135.4, 128.6 (2C), 128.2, 126.6 (2C), 123.4, 77.1, 62.0, 61.9,
4.2. General procedure 1. Michael addition of 1,3-dicarbonyl
compounds to nitrodienes using DBU as catalyst
1,3-Dicarbonyl compound 8a–c or 11a–c (0.5 mmol) was added
to the corresponding nitrodiene 9a–h (0.25 mmol) in toluene
(0.5 mL) and the reaction mixture was stirred for 10 min. Next,
53.6, 41.2, 14.0 (2C) ppm; IR (CHCl3, film):
2874, 1732, 1556, 1465, 1448, 1371, 1030, 970, 784, 694 cmꢁ1
the enantiomeric excess was determined by HPLC with a Daicel
m = 3026, 2981, 2938,
;

520
R. Chowdhury et al. / Tetrahedron: Asymmetry 25 (2014) 516–522
chiralpak AD-H column [k = 220 nm], eluent:2-propanol/hexane
(10/90), flow rate = 0.8 mL/min, tminor = 20.57 min (4.88%),
tmajor = 22.55 min (95.12%).
1731, 1556, 1492, 1435, 1378, 1093, 972, 753 cmꢁ1; elemental
analysis calcd (%) for C15H16ClNO6: calcd C 52.72, H 4.72, N 4.10;
found: C 52.53, H 4.48, N 4.29; the enantiomeric excess was deter-
mined by HPLC with a Daicel chiralpak OD-H column [k = 220 nm],
4.7. (S)-Methyl-2-carbomethoxy-3-(nitromethyl)-5-(2-methoxy-
eluent: 2-propanol/hexane (5/95), flow rate
= 0.8 mL/min,
phenyl)-4-pentenoate 10c
tminor = 41.9 min (7.33%), tmajor = 49.09 min (92.67%).
White solid; Yield: 63 mg (75%); Recrystallized from hexane–
4.11. (S)-Ethyl-2-carboethoxy-3-(nitromethyl)-5-(4-chlorophenyl-
EtOAc; Yield: 42 mg (50%); mp 53–55 °C (hexane–EtOAc);
4-pentenoate 10g
½
a 2D5
ꢂ
¼ ꢁ12:0 (c 0.6, CHCl3) >99% ee; 1H NMR (200 MHz, CDCl3):
d = 7.18–7.36 (m, 2H), 6.81–6.92 (m, 3H), 6.01–6.17 (m, 1H),
4.63–4.81 (m, 2H), 3.81 (s, 3H), 3.76 (s, 4H), 3.73 (s, 4H) ppm;
13C NMR (50 MHz, CDCl3): d = 167.8, 167.6, 156.7, 130.4, 129.3,
127.0, 124.9, 123.7, 120.6, 110.8, 77.05, 55.4, 53.5, 52.8 (2C),
Yellow solid; Yield: 85 mg (91%); Recrystallized from hexane–
EtOAc; Yield: 42 mg (45%); mp 62–64 °C (hexane–EtOAc);
½
a 2D6
ꢂ
¼ ꢁ21:4 (c 1.4, CHCl3) 99% ee; 1H NMR (200 MHz, CDCl3):
d = 7.20 (m, 4H), 6.52 (d, J = 15.8 Hz, 1H), 6.09 (dd, J = 8.8, 15.8 Hz,
1H), 4.61–4.80 (m, 2H), 4.16–4.27 (m, 4H), 3.62–3.79 (m, 2H), 1.24
(q, J = 7.2 Hz, 6H) ppm; 13C NMR (50 MHz, CDCl3): d = 167.2, 167.1,
134.3, 134.2, 133.9, 128.8 (2C), 127.8 (2C), 124.2, 77.0, 62.1, 62.0,
41.6 ppm; IR (CHCl3, film):
m = 2985, 2877, 1740, 1554, 1465,
1448, 1255, 1030, 970, 784 cmꢁ1; elemental analysis calcd (%) for
C16H19NO7: C 56.97, H 5.68, N, 4.15; found: C 57.15, H 5.50, N
4.09; the enantiomeric excess was determined by HPLC with a Dai-
cel chiralpak AD-H column [k = 220 nm], eluent: 2-propanol/hex-
ane (10/90), flow rate = 0.8 mL/min, tminor = 21.1 min (0.28%),
tmajor = 24.10 min (99.72%).
53.5, 41.2, 14.0 (2C) ppm IR (KBr):
m = 2980, 2877, 2843, 1747,
1550, 1472, 1374, 1259, 1154, 1012, 936, 745 cmꢁ1; elemental anal-
ysis calcd (%) for C17H20ClNO6: C 55.21, H 5.45, N 3.79; found: C
55.60, H, 5.24, N 3.98; the enantiomeric excess was determined by
HPLC with a Daicel chiralpak OD-H column [k = 220 nm], eluent:
2-propanol/hexane (5/95), flow rate = 0.8 mL/min, tminor = 21.90
min (0.52%), tmajor = 25.33 min (99.48%).
4.8. (S)-Methyl-2-carbomethoxy-3-(nitromethyl)-5-(4-nitrophenyl)-
4-pentenoate 10d
Yellow solid; Yield: 62 mg (70%); mp 97–99 °C; ½a D24
ꢂ
¼ ꢁ13:3 (c
4.12. Dimethyl 2-(R,E)-3-methyl-1-nitro-4-phenylbut-3-en-2-yl)
malonate 10h
0.75, CHCl3) 76% ee; 1H NMR (200 MHz, CDCl3): d = 8.15 (d,
J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 15.8 Hz, 1H),
6.30 (dd, J = 8.6, 15.8 Hz, 1H), 4.71–4.75 (m, 2H), 3.77 (s, 3H),
3.74 (s, 3H), 3.71–3.77 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3):
d = 167.4 (2C), 147.4, 142.0, 133.4, 128.4, 127.3 (2C), 124.0 (2C),
Colorless oil; Yield: 53 mg (66%); ½a D27
¼ ꢁ20:5 (c 1.9, CHCl3) 80%
ꢂ
ee; 1H NMR (200 MHz, CDCl3): d = 7.25–7.35 (m, 3H); 7.12–7.24 (m,
2H), 6.43 (br s, 1H), 4.65–4.83 (m, 2H), 3.78 (s, 3H), 3.74–3.76 (m,
2H), 3.72 (s, 3H), 1.86 (d, J = 1.0 Hz, 3H) ppm; 13C NMR (50 MHz,
CDCl3): d = 168.0, 167.4, 136.6, 132.3, 131.0, 128.8 (2C), 128.1 (2C),
76.6, 53.07, 53.02, 52.97, 41.1 ppm; IR (KBr):
m = 2985, 2843,
1740, 1600, 1552, 1515, 1438, 1348, 1322, 1262, 1163, 973,
745 cmꢁ1; HRMS (ESI): m/z: calcd for C15H16N2O8Na [M+Na]+:
375.0790; found: 375.0799; elemental analysis calcd (%) for
127.0, 75.7, 53.0, 52.9, 52.7, 46.5, 15.1 ppm; IR (film):
m = 2954,
2914, 1735, 1552, 1492, 1435, 1329, 1028, 746 cmꢁ1; elemental
analysis calcd (%) for C16H19NO6: calcd C 59.81, H 5.96, N 4.36;
found: C 59.51, H 6.26, N 4.16. The enantiomeric excess was deter-
mined by HPLC with a Daicel chiralpak OD-H column [k = 220 nm],
eluent: 2-propanol/hexane (5/95), flow rate = 0.5 mL/min,
tmajor = 47.17 min (90.29%), tminor = 57.25 min (9.71%).
C
15H16N2O8: C 51.14, H 4.58, N 7.95; found: C, 50.97; H, 4.58; N,
8.32; The enantiomeric excess was determined by HPLC with a
Daicel chiralpak OD-H column [k = 220 nm], eluent: 2-propanol/
hexane (10/90), flow rate = 1.0 mL/min, tminor = 80.97 min
(12.14%), tmajor = 87.74 min (87.76%).
4.9. (S)-Methyl-2-carbomethoxy-3-(nitromethyl)-5-(4-bromo-
4.13. (S)-Methyl-2-carbomethoxy-3-(nitromethyl)-5-(3-bromo-
phenyl)-4-pentenoate 10e
phenyl)-4-pentenoate 10i
Light yellow oil; Yield: 84 mg (87%); ½a D24
ꢂ
¼ ꢁ11:3 (c 2.3, CHCl3)
Yellow oil; Yield: 91 mg (95%);½a D23
¼ ꢁ7:7 (c 2.2, CHCl3) 85%
ꢂ
84% ee; 1H NMR (200 MHz, CDCl3): d = 7.39–7.43 (m, 3H); 7.17 (d,
J = 8.4 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 6.02–6.15 (m, 1H), 4.60–
ee; 1H NMR (200 MHz, CDCl3): d = 7.39–7.45 (m, 1H), 7.35–7.38
(m, 1H), 7.11–7.24 (m, 2H), 6.50 (d, J = 15.8 Hz, 1H), 6.04–6.19
(m, 1H), 4.61–4.79 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.67–3.70
(m, 2H) ppm; 13C NMR (50 MHz, CDCl3): d = 167.5, 167.5, 137.9,
134.1, 131.2, 130.1, 129.4, 126.8, 125.3, 124.9, 76.8, 53.2, 53.0,
4.78 (m, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.67–3.75 (m, 2H) ppm; 13
NMR (50 MHz, CDCl3): d = 167.5, 167.4, 134.7, 134.3, 131.7 (2C),
C
128.1 (2C), 124.1, 122.1, 76.8, 52.92, 52.9, 51.1, 41.2 ppm; IR (film):
m
= 3025, 2955, 1737, 1556, 1435, 1378, 1162, 1072, 969, 753 cmꢁ1
;
52.95, 41.1 ppm; IR (film):
1378, 1161, 1072, 970, 753 cmꢁ1; elemental analysis calcd (%) for
15H16BrNO6: C 46.65, H 4.18, N, 3.63; found: C 46.56, H 4.04, N
m = 3026, 2954, 1736, 1557, 1435,
elemental analysis calcd (%) for C15H16BrNO6: C 46.65, H 4.18, N
3.63; found: C 46.26, H 4.05, N 3.95; The enantiomeric excess was
C
determined by HPLC with
[k = 220 nm], eluent: 2-propanol/hexane (10/90), flow rate = 0.8
mL/min, tminor = 31.69 min (8.01%), tmajor = 41.43 min (91.99%).
a
Daicel chiralpak OD-H column
4.11; the enantiomeric excess was determined by HPLC with a Dai-
cel chiralpak AD-H column [k = 220 nm], eluent: 2-propanol/hex-
ane (10/90), flow rate = 0.8 mL/min, tminor = 22.0 min (7.36%),
tmajor = 34.82 min (92.64%).
4.10. (S)-Methyl-2-carbomethoxy-3-(nitromethyl)-5-(4-chloro-
phenyl)-4-pentenoate 10f
4.14. (4E)-Dimethyl 2-[(S)-4,8-dimethyl-1-nitronona-3,7-dien-2-yl]
malonate 10j
Light yellow oil; Yield: 79 mg (93%); ½a D27
¼ ꢁ15:6 (c 0.9, CHCl3)
ꢂ
86% ee; 1H NMR (200 MHz, CDCl3): d = 7.18–7.32 (m, 4H); 6.52 (d,
J = 15.8 Hz, 1H), 6.01–6.14 (m, 1H), 4.61–4.79 (m, 2H), 3.76 (s, 3H),
3.72 (s, 3H), 3.67–3.76 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3):
d = 167.6, 167.5, 134.3, 133.9, 129.3, 129.2, 128.7 (2C), 127.8 (2C),
Yellow oil; Yield: 62 mg (76%); E:Z ꢀ 6/4; ½a D27
¼ ꢁ9:0 (c 1.0,
ꢂ
CHCl3) 72% ee; 1H NMR (200 MHz, CDCl3, E:Z ꢀ 6/4): d = 4.95–
5.04 (m, 2H), 4.62 (dd, J = 4.9, 12.2 Hz, 1H), 4.44 (dd, J = 8.4,
12.2 Hz, 1H), 3.86–3.92 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.50 (d,
J = 8.0 Hz, 1H), 1.97–2.04 (m, 4H), 1.66 (s, 6H), 1.55 (s, 3H) ppm;
124.0, 76.8, 53.2, 52.9, 41.2 ppm; IR (film):
m = 2955, 2925, 2847,

R. Chowdhury et al. / Tetrahedron: Asymmetry 25 (2014) 516–522
521
13C NMR (50 MHz, CDCl3, E:Z ꢀ 6/4): d = 168.0 (E). 167.9 (Z), 167.8
(E), 167.7 (Z), 143.0 (E), 142.8 (Z), 132.4 (Z), 131.9 (E), 123.6 (Z),
123.4 (E), 119.3 (Z), 118.7 (E), 77.4 (E), 77.3 (Z), 53.6 (Z), 53.4 (E),
52.7 (2 C, E), 52.6 (2 C, Z), 39.7 (E), 36.6 (E), 36.3 (Z), 32.0 (Z),
26.3, 25.6 (Z), 25.5 (E), 23.4 (Z), 17.6 (E), 17.5 (Z), 16.3 (E) ppm;
tmajor (diast-2) = 69.00 min (41.79%), tminor (diast-2) = 77.90 min
(3.78%), tmajor (diast-1) = 142.20 min (49.26%).
4.18. (3S)-Methyl 2-acetyl-3-(nitromethyl)-5-phenyl-2-(prop-2-
ynyl)pent-4-enoate 12c
IR (film):
m = 2956, 2922, 2856, 1739, 1632, 1556, 1435, 1378,
1257, 1160, 1016, 912, 733 cmꢁ1; HRMS (ESI): m/z calcd for C16H25-
NO6Na [M+Na]+: 350.1575; found: 350.1574; the enantiomeric ex-
cess was determined by HPLC with a Daicel chiralpak AD-H column
[k = 220 nm], eluent: 2-propanol/hexane (5/95), flow rate = 0.5 mL/
min, tminor = 12.58 min (14.16%), tmajor = 14.43 min (85.84%).
Yellow oil; Yield: 78 mg (95%); 1H NMR (200 MHz, CDCl3, ꢀ7:3
mixture of diastereoisomers): d = 7.23–7.32 (m, 5H), 6.63 (d, 1H,
J = 15.8 Hz, minor), 6.55 (d, 1H, J = 15.8 Hz, major), 6.00 (dd, 1H,
J = 9.8, 15.6 Hz, major), 5.80 (dd, 1H, J = 10.2, 15.8 Hz, minor),
4.88–4.98 (m, 1H), 4.66 (dd, 1H, J = 10.8, 12.6 Hz, major), 4.46
(dd, 1H, J = 10.8, 12.6 Hz, minor), 3.84–4.01 (m, 1H), 3.83 (s, 3H,
minor), 3.75 (s, 3H, major), 2.99 (dd, 1H, J = 2.6, 17.6 Hz, major),
2.73–2.88 (m, 1H, major, 2 H minor), 2.24 (s, 3H), 2.16 (t, 1H,
J = 1.6 Hz) ppm; 13C NMR (50 MHz, CDCl3, ꢀ7:3 mixture of diaste-
reoisomers): d = 202.0 (major), 201.0 (minor), 169.6, 137.1 (minor),
136.7 (major), 135.8 (major), 135.7 (minor), 128.6 (2C), 128.4
(minor), 128.3 (major), 126.7 (2 C, minor), 126.6 (2 C, major),
122.2 (major), 121.6 (minor), 78.5 (minor), 76.7 (major), 73.3,
64.4 (major), 63.7 (minor), 53.2 (major), 53.1 (minor), 45.5 (major),
43.8 (minor), 29.6, 27.8 (major), 27.1 (minor), 22.9 (minor), 22.0
4.15. Dimethyl 2-allyl-2-((S,E)-1-nitro-4-phenylbut-3-en-2-yl)
malonate 10k
Yellow oil; Yield: 40 mg (45%);½a D23
ꢂ
¼ þ20:9 (c 2.2, CHCl3); 1H
NMR (200 MHz, CDCl3): d = 7.24–7.32 (m, 5H), 6.54 (d,
J = 15.6 Hz, 1H), 5.62–5.77 (m, 2H), 5.07–5.18 (m, 2H), 4.90 (dd,
J = 2.9, 12.7 Hz, 1H), 4.50 (dd, J = 10.8, 12.6 Hz, 1H), 3.80 (s, 3H),
3.76 (s, 3H), 3.69 (dd, J = 3.0, 10.4 Hz, 1H), 2.60–2.82 (m,
2H) ppm; 13C NMR (50 MHz, CDCl3): d = 169.9, 169.7, 136.9,
135.8, 131.4, 128.6 (2C), 128.3, 126.6 (2C), 122.1, 120.1, 77.6,
(major) ppm; IR (film):
m = 3306, 2955, 2925, 2852, 2255, 1719,
59.5, 52.8, 52.7, 44.9, 38.5 ppm; IR (film):
m
= 3081, 3027, 2954,
1556, 1449, 1434, 1224, 970, 731 cmꢁ1; HRMS (ESI): m/z calcd
for C18H19NO5Na [M+Na]+: 352.1156; found: 352.1155; The enan-
tiomeric excess was determined by HPLC with a Daicel chiralpak
AD-H column [k = 220 nm], eluent: 2-propanol/hexane (5/95), flow
2846, 1729, 1641, 1556, 1495, 1434, 1378, 970, 920, 748 cmꢁ1; ele-
mental analysis calcd (%) for C18H21NO6: C 62.24, H 6.09, N 4.03;
found: C 62.03, H 5.75, N 4.06; the enantiomeric excess was deter-
mined by HPLC with a Daicel chiralpak OD-H column [k = 220 nm],
eluent: 2-propanol/hexane (5/95), flow rate = 0.5 mL/min,
tminor = 25.44 min (8.51%), tmajor = 43.74 min (91.49%).
rate = 0.5 mL/min, tminor
diast) = 27.92 min (2.63%), tmajor
(minor
(minor
diast) = 29.35 min (24.29%), tminor
diast) = 30.45 min (16.97%),
(major
tmajor (major diast) = 34.40 min (56.10%).
4.16. 3-((S,E)-1-Nitro-4-phenylbut-3-en-2yl) pentane-2,4-dione
4.19. (3S,4S)-Methyl 2-oxo-4-styrylpyrrolidine-3-carboxylate 13
12a
Zinc powder (570 mg, 8.8 mmol) was added portionwise to a
stirred solution of nitroester 10a (77 mg, 0.25 mmol, 88% ee) in
2:1 THF/acetic acid (3 mL) at room temperature. After 3 h, the reac-
tion mixture was filtered through a Celite pad and the filtrate was
evaporated under reduced pressure followed by high vacuum. The
residue was dissolved in dichloromethane (3 mL) and an aqueous
saturated solution of sodium bicarbonate (1 mL) was added into
it. The reaction mixture was stirred at room temperature for
20 h, extracted with dichloromethane and the organic extract
was evaporated under reduced pressure. The residue was purified
by column chromatography to give lactam 13 (52 mg, 85%) as
White solid; Yield: 63 mg (92%); Recrystallized from hexane–
EtOAc; Yield: 36 mg (53%); mp 143–145 °C (hexane–EtOAc);
½
a 2D6
ꢂ
¼ ꢁ203 (c 1.0, CHCl3) >96% ee; 1H NMR (200 MHz, CDCl3):
d = 7.29–7.31 (m, 5H), 6.54 (d, J = 15.8 Hz, 1H), 6.00 (dd, J = 9.4Hz,
1H), 4.53 (d, J = 6 Hz, 2H), 4.05 (d, J = 11 Hz, 1H), 3.64–3.79 (m,
1H), 2.27 (s, 3H), 2.19 (s, 3H) ppm; 13C NMR (50 MHz, CDCl3):
d = 201.8, 201.6, 135.5, 135.5, 128.6 (2C), 128.4, 126.5 (2C), 123.1,
ꢀ
77.3, 68.9, 40.9, 30.5, 29.9 ppm; IR (KBr): U = 2985, 2878, 2844,
1729, 1704, 1553, 1356, 1268, 1146, 970, 744 cmꢁ1; elemental
analysis calcd (%) for C15H17NO4: C 65.44, H 6.22, N 5.09; found:
C 65.39, H 5.88, N 5.05; the enantiomeric excess was determined
by HPLC with a Daicel chiralpak AD-H column [k = 220 nm], eluent:
2-propanol/hexane (5/95), flow rate = 0.5 mL/min, tminor = 26.12 -
min (1.84%), tmajor = 32.61 min (98.16%).
white flakes. mp 140–143 °C; ½a D26
ꢂ
¼ ꢁ127:4 (c 0.31, CHCl3); 1H
NMR (200 MHz, CDCl3): d = 7.18–7.36 (m, 5H), 7.15 (br s, 1H),
6.53 (d, J = 15.6 Hz, 1H), 6.12 (dd, J = 7.8, 15.8 Hz, 1H), 3.79 (s,
3H), 3.53–3.75 (m, 2H), 3.35 (d, J = 9.2 Hz, 1H), 3.24 (t, J = 8.0 Hz,
1H) ppm; 13C NMR (50 MHz, CDCl3): d = 172.9, 169.4, 136.1,
132.6, 128.6 (2C), 127.9, 127.2, 126.3 (2C), 53.9, 52.8, 46.2,
4.17. (3S)-Methyl 2-acetyl-3-(nitromethyl)-5-phenylpent-4-
enoate 12b
42.8 ppm; IR (CHCl3, film): m = 3348, 3054, 3020, 2951, 1791,
1696, 1490, 1449, 1434, 1346, 1270, 1213, 1168, 1049, 997, 926,
754 cmꢁ1; elemental analysis calcd (%) for C14H15NO3: calcd C
68.56, H 6.16, N 5.71; found: C 68.69, H 6.46, N 5.27.
White solid; Yield: 65.5 mg (90%); 1H NMR (200 MHz, CDCl3,
ꢀ1:1 mixture of diastereoisomers): d = 7.27–7.29 (m, 10H), 6.55
(dd, J = 2, 16 Hz, 2H), 6.07 (dd, J = 3, 15.8 Hz, 1H), 6.02 (dd, J = 3,
15.8 Hz, 1H), 4.59–4.76 (m, 4H), 3.77 (s, 3H), 3.71 (s, 3H),
3.70–3.88 (m, 4H), 2.30 (s, 3H), 2.26 (s, 3H) ppm; 13C NMR
(50 MHz, CDCl3, ꢀ1:1 mixture of diastereoisomers): d = 200.9,
200.8, 168.0, 167.8, 135.8, 135.7, 135.5, 135.2, 128.6 (4C), 128.3,
128.2, 126.5 (4C), 123.4 (2C), 77.1 (2C), 60.5, 60.1, 30.3, 52.8
Acknowledgements
Mr. G.B.V. is thankful to University Grants Commission (UGC),
New Delhi for a JRF.
(2C), 40.8, 40.5, 30.1 ppm; IR (CHCl3, film):
3020, 2951, 1791, 1696, 1490, 1449, 1434, 1346, 1270, 1213,
1168, 1049, 997, 926, 754 cmꢁ1
HRMS (ESI): m/z calcd
for
15H17NO5Na [M+Na]+ 314.0994; found: 314.0999; the
enantiomeric excess was determined by HPLC with a Daicel
chiralpak AS-H column [k = 220 nm], eluent: 2-propanol/hexane
(5/95), flow rate = 0.5 mL/min, tminor (diast-1) = 52.00 min (5.17%),
m = 3348, 3054,
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;
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