Enantioselective organocatalytic Michael reactions using chiral (R,R)-1,2-diphenylethylenediamine-derived thioureas

Article abstract of DOI:10.1039/d0ra03550e

Although the Michael addition is a very well-known and widely applied reaction, cost-effective, metal-free, and readily prepared organic catalysts remain rare. A chiral, bifunctional, (R,R)-1,2-diphenylethylenediamine-derived thiourea organic catalyst was

Full text of DOI:10.1039/d0ra03550e

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Enantioselective organocatalytic Michael reactions
using chiral (R,R)-1,2-diphenylethylenediamine-
derived thioureas†
Cite this: RSC Adv., 2020, 10, 31808
a
a
a
b
*
Min Ji Lee, Min Ho Lee, Byeong-Seon Kim
Jae Ho Shim,
and Deok-Chan Ha
a
*
Although the Michael addition is a very well-known and widely applied reaction, cost-effective, metal-free,
and readily prepared organic catalysts remain rare. chiral, bifunctional, (R,R)-1,2-
A
diphenylethylenediamine-derived thiourea organic catalyst was developed and applied to asymmetric
Michael additions of nitroalkenes under neutral conditions. Generally, fluorine-substituted thiourea
catalysts exhibited high chemical yields and enantioselectivities under neutral conditions. The mild
reactions were tolerant of many functional groups and afforded good-to-excellent yields, as well as high
diastereo- and enantioselectivities for the Michael adducts. The utility of the transformation was
demonstrated by the synthesis of a bioactive compound, (R)-Phenibut.
Received 20th April 2020
Accepted 20th August 2020
DOI: 10.1039/d0ra03550e
rsc.li/rsc-advances
despite its high synthetic potential, the number of highly ster-
eoselective Michael-addition-based synthetic methods is
limited.6,7 Nitro-group-containing Michael acceptors are very
attractive due to their highly electron-decient properties and
because the nitro group is easily converted into other functional
groups, including ketones, esters, amine, and carboxylic acids
(Fig. 1).5
The Takemoto group reported high enantioselectivity in
a Michael reaction involving a malonate and nitroalkene using
an (R,R)-1,2-cyclohexyldiamine-thiourea-based catalyst.8 In
another study, they obtained high enantio- and diaster-
eoselectivities using a thiourea-derived catalyst in a Michael
Introduction
Numerous studies on metal-free stereoselective organic cata-
lysts have been reported over the past century.1 Although ster-
eoselective metal-catalyzed reactions generally provide more
reliable results than those catalyzed by organic compounds,
metal catalysts are disadvantageous in several respects. They are
typically expensive, which leads to higher production costs.2
Moreover, the metal waste remaining aer completion of the
reaction can contaminate both the product and/or the envi-
ronment.3 To overcome these drawbacks, stereoselective
syntheses using metal-free organic catalysts are becoming
increasingly important. With this in mind, our group has been
motivated to examine organic catalysts from a variety of
perspectives, and we previously reported the application of
a thiourea catalyst derived from (R,R)-1,2-diphenylethane-1,2-
diamine (DPEN)4 in several reactions.
Compounds with adjacent quaternary and tertiary stereo-
centers can be prepared by Michael additions to electron-
decient olens, as exemplied by the reactions of trisubsti-
tuted carbon nucleophiles with nitroalkenes; these products
can serve as building blocks for the syntheses of complex
natural materials. In this regard, the Michael reaction is one of
the most important C–C bond-forming reactions. However,
aLaboratory of Organic Synthesis, Department of Chemistry, Research Institute for
Natural Sciences, Korea University, Seoul 136-713, Korea. E-mail: dechha@korea.ac.
kr
bDepartment of Chemistry Education, Research Institute of Natural Science,
Gyeongsang National University, Jinju 52828, Korea. E-mail: bkim@gnu.ac.kr
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra03550e
Fig. 1 Transformations of nitro compounds.
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reaction involving a b-ketoester and nitroalkene.9 Cavallo and bearing an electron-donating p-tolyl substituent gave product 4c
co-workers recently explored the use of hexauorobenzene with slightly lower enantioselectivity (60%) than 1b–1d, which
(C6F6) as the solvent in a study into the asymmetric Michael contained electron-withdrawing groups (entries 2–5). However,
reaction of a b-ketoester and nitroalkene.10 Conventionally, the use of catalyst 1g, which also contained an electron-
hydrogen-bond-forming noncovalent catalysts afford good withdrawing group, led to much lower enantio-selectivity than
stereoselectivities in nonpolar solvents such as toluene. On the that of 1e (entry 5), which indicates that the electronic nature of
other hand, hexa-uorobenzene (3 ¼ 2.05) stabilizes the enol the R2 group does not necessarily determine the outcome of the
form of the b-keto ester through p-stacking, which may lead to reaction. Overall, the catalysts bearing electron-withdrawing
good reactivity and stereoselectivity.
substituents provide higher enantioselectivities than those
Herein, we report on the catalytic activities of new chiral with electron-donating groups. Aer securing the highest
organocatalysts based on (R,R)-DPEN-derived thioureas11 in the enantioselectivity with pentauorophenyl-substituted catalyst
asymmetric Michael addition reactions of nitroalkenes.
1h (Table 1, entry 8), Again, the 3-pentyl-substituted catalyst
provided the highest enantioselectivity among the catalysts
investigated.
We next probed the effect of lower reaction temperatures
using catalyst 1h; unfortunately, lower enantioselectivities were
obtained than at room temperature (entries 10–11). Based on
the results summarized in Table 1, we conclude that the optimal
reaction conditions involve the use of the pentauorophenyl-
substituted catalyst 1h at room temperature (Table 1, entry 8).
With the optimal catalyst and temperature conditions in
hand, we examined the effect of solvent on reactivity and
enantioselectivity (Table 2). Other than hexane, good overall
enantioselectivities were obtained in all the solvents examined.
Although the best diastereoselectivity was observed in tri-
uorotoluene (Table 1, entry 5), the catalyst was less enantio-
selective in this solvent than in toluene, and the reaction took
longer for a lower yield (Table 1, entry 2). Therefore, we selected
the optimal solvent as toluene with a reaction time of 12 h.
The Michael addition reactions of a variety of b-ketoesters
with trans-b-nitrostyrene mediated by catalyst 1h were surveyed
(Scheme 1). Good overall enantioselectivities were observed
regardless of the substituent on the b-keto ester; however, the
product yields were poor when cyclohexanone 2e, cyclo-
heptanone 2f, and a-tetralone 2h were used as substrates. The
results also show that 4a was produced from ethyl acetoacetate 2a
with low diastereoselectivity, which is ascribed to epimerization.
Results and discussion
The Michael addition reaction of trans-b-nitrostyrene 3a with 2-
carboxyethylcyclopentanone 2a was rst screened with catalyst
1a under neutral conditions. This catalyst is a highly basic N-
monosubstituted thiourea that lacks an alkyl group (R1 ¼ H) on
the amine of the DPEN unit (Table 1). Catalyst effectiveness was
initially investigated at room temperature in CH2Cl2, affording
the desired product with 29% ee (Table 1, entry 1). This result
suggests that the catalyst can impart stereoselectivity to some
extent even without an alkyl group (R1) on the terminal amine.
Subsequent reactions were performed with 3-pentyl-substituted
thiourea catalysts 1b–1h.
To increase the potential for hydrogen bonding via the
hydrogen atoms of the thiourea, we adjusted their acidities by
introducing different groups (R2) on the urea moiety. Catalyst 1e
Table 1 Catalyst and temperature optimization
Table 2 Solvent optimization
Entry
Cat.
Temp (ꢀC)
Yielda (%)
drb
eeb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
0
98
90
94
94
83
89
88
99
91
96
96
87 : 13
66 : 44
70 : 30
93 : 7
92 : 8
96 : 4
74 : 26
95 : 5
96 : 4
97 : 3
98 : 2
29
67
78
73
60
68
50
93
15
83
91
Entry
Solvent
Time (h)
Yielda (%)
drb
eeb (%)
1
2
3
4
5
6
Hexane
Toluene
Et2O
THF
Triuorotoluene
CH2Cl2
12
12
12
96
72
12
74
87
75
67
76
99
95 : 5
98 : 2
97 : 3
95 : 5
99 : 1
95 : 5
62
97
95
92
94
93
9
10
11
1h
1h
ꢁ30
a
b
a
b
Isolated yield. Determined by chiral-phase HPLC using an OD-H
column.
Isolated yields. Determined by chiral-phase HPLC using an OD-H
column.
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Table 4 Michael reactions using catalyst 1d (R1 ¼ 3-pentyl; R2 ¼ 3,5-
di-CF3-C6H3)
Entry
R1
R2
Product
Yielda [%]
eeb [%]
1
Me
Et
Et
i-Pr
n-Pr
n-Pr
Bu
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Br-Ph
4-Cl-Ph
4-Me-Ph
4-MeO-Ph
2-MeO-Ph
4-HO-Ph
Furyl
5a
5b
5b
5c
5d
5d
5e
5f
5g
5h
5i
5j
5k
5l
89
85
86
49
45
98
41
77
72
60
40
51
40
78
80
90
78
99
98
99
94
88
89
84
89
70
89
72
Scheme 1 Asymmetric Michael additions of b-ketoesters to trans-b-
nitrostyrene. aIsolated yield. bDetermined by HPLC using a chiral
column.
2
3c
4
5
6d
7
Various nitroalkenes 3 were reacted with methyl 2-oxo-
cyclopentanecarboxylate (2d) and methyl 2-oxocyclohexane-
carboxylate (2e) (Table 3). Good enantioselectivities were
observed when nitroalkenes 3 were reacted with 2d, regardless
of whether the substituent was electron-withdrawing or
electron-donating. However, lower yields were obtained when
trans-nitroolens bearing ortho-substituted aromatic substitu-
ents or aliphatic substituents were used. Good enantioselectiv-
ities were observed when 2e was reacted with nitroalkenes
bearing both electron-withdrawing and electron-donating
substituents. As previously observed, lower yields of 4 were
obtained with 2e than with 2d.
8
9
10
11
12
13
14
Et
Et
a
Isolated yield. b Determined by chiral HPLC. c Using the 1h catalyst for
reaction. d In CH2Cl2 for 12 h heated at reux.
because when use 1h catalyst in this reactions, it give more
lower ee than 1d catalyst. Although good overall yields and
enantioselectivities were obtained, the yields decreased with the
increasing size and length of the malonate ester groups (R1)
(Table 4, entries 1–6). These results suggest that the reaction
rate decreases with increasing steric bulk of the malonate
substituent. Further experiments were performed using diethyl
malonate and various b-nitrostyrenes.11 The product and ee
yields were generally lower than those obtained using the
parent b-nitrostyrene (Table 4, entries 7–13); however, good
yields and enantioselectivities were obtained for b-nitrostyrenes
with electron-withdrawing 4-bromo and 4-chloro substituents.
In contrast, lower yields and enantioselectivities were observed
for b-nitrostyrenes substituted with electron-donating 4- and 2-
methoxy groups. These results indicate that b-nitrostyrenes
bearing electron-withdrawing groups are better Michael accep-
tors toward the nucleophile because the double bond is more
electron-decient, which facilitates nucleophilic attack. We
tested recycling of the catalysts 1h (Fig. 2, ESI Table 1†). In these
Finally, to fully explore substituent effects in these reactions,
variously substituted malonates and nitroalkenes were sub-
jected to the reaction. In these cases, we used catalyst 1d
Table 3 Asymmetric Michael additions of cyclic b-ketoesters to nitro-
olefins
Entry
2
R1
4
Yielda (%)
drb
eeb (%)
1
2
3
4
5
6
7
8
2d
2d
2d
2d
2d
2d
2d
2d
2d
2e
2e
2e
2e
2e
Ph
4d
4i
4j
4k
4l
4m
4n
4o
4p
4e
4q
4r
92
85
85
88
92
25
60
42
41
25
24
50
26
19
96 : 4
88 : 12
96 : 4
96 : 4
93 : 7
98 : 2
99 : 1
99 : 1
99 : 1
98 : 2
95 : 5
99 : 1
99 : 1
99 : 1
99
90
98
98
96
92
98
98
98
92
98
98
94
80
p-Tolyl
4-Cl-Ph
4-Br-Ph
4-MeO-Ph
2-MeO-Ph
Bu
Cyclohexyl
i-Pr
Ph
p-Tolyl
4-Cl-Ph
4-Br-Ph
4-OMe-Ph
9
10
11
12
13
14
4s
4t
a
Isolated yields. b Determined by HPLC using a chiral column.
Fig. 2 Recycling test for asymmetric Michael addition using chiral
(R,R)-1,2-diphenylethylenediamine-derived thiourea catalyst (1d).
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make it possible to infer the role of the catalyst in enabling the
reaction (Fig. 3).
In the transition state involved in the present catalytic
reaction, the nitro atoms of the thiourea group of the catalyst
form hydrogen bonds with the oxygen atoms of the nitroalkene,
xing its position and increasing the reactivity of the electro-
philic double bond. Additionally, the enol form of the malonate
interacts via hydrogen bonding with the free amino group of the
catalyst, situating it for attack of the nitroalkene from behind to
form the (R)-product.
Scheme 2 Synthesis of the inhibitory neurotransmitter Phenibut.
Conclusions
The Michael additions of 1,3-dicarbonyl compounds to nitro-
alkenes catalyzed by N-monosubstituted thiourea derivatives of
DPEN provided products with good-to-excellent enantio- and
diastereoselectivities. These catalysts are cost-effective because
they are more readily prepared than conventional organic
catalysts. The Michael adducts possessed adjacent quaternary
and tertiary stereocenters and were obtained in relatively good
yields. Furthermore, since the g-lactone intermediate prepared
by this reaction can be used as an intermediate for the prepa-
ration of anti-depressant drugs, further studies on its medical
applications must be conducted, due to the increasing need for
investigations of the medical and biological applications of
such compounds.
four times test, we obtained data for the (R,R)-1,2-
diphenylethylenediamine-derived thiourea catalyst (1d) could
be recyclable (Scheme 2).
Based on the foregoing results, we envisioned that these
Michael addition products would provide access to bioactive
compounds such as the inhibitory neurotransmitter and anti-
depressant, (R)-Phenibut® (6a, Scheme 2).12,13 To achieve this
objective, we used previously prepared adduct 5d from the
reaction of n-propyl malonate with b-nitrostyrene.
The nitro group of 5d was reduced with NiCl2$6H2O and
NaBH4 (Scheme 2), which resulted in formation of a cyclic
amide, i.e., an ester-bearing pyrrolidinone. Pyrrolidinone ring
opening and decarboxylation were achieved by treatment with
HCl, which afforded b-phenyl-g-aminobutanoic acid (GABA)
derivative 6a.11
The experimental results obtained for the stereoselective
Michael addition reactions using malonate derivatives and
nitroalkenes provide insight into the reaction mechanism and
Experimental
General procedure for the asymmetric Michael reaction (4a–
4t)
The b-nitrostyrene (1.2 equiv.), b-ketoester (2.0 equiv.), and 1d
(10 mol%) were mixed in toluene (0.4 M) and the reaction
mixture was stirred at ambient temperature. The reaction
conversion was monitored by TLC. Aer completion, ethyl
acetate (0.2 mL) was added in the reaction mixture. This solu-
tion was washed twice with water (2 ꢂ 1.0 mL), dried over
magnesium sulfate, and concentrated to yield the desired
product. The product was puried by chromatography on
a silica-gel column (hexanes/ethyl acetate 5 : 1).
Ethyl 2-acetyl-4-nitro-3-phenylbutanoate (4a). Colorless oil;
[a]2D0 ¼ ꢁ196.3 (c ¼ 0.0575, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.30 (m, 3H), 7.21 (d, J ¼ 6.6 Hz, 2H), 4.80 (m, 2H), 4.22 (m,
1.8H), 4.12 (d, J ¼ 10.1 Hz, 0.6H), 4.03 (d, J ¼ 9.0 Hz, 0.4H), 3.96
(q, J ¼ 15 Hz, 1.2H), 2.30 (s, 1.6H), 2.06 (s, 1.4H), 1.28 (t, J ¼
15.0 Hz, 1.2H), 1.00 (t, J ¼ 12.0 Hz, 1.8H); 13C NMR (100 MHz,
CDCl3) d 201.3, 200.5, 167.7, 167.0, 136.6, 136.5, 129.3, 129.1,
128.4, 128.1, 78.1, 78.0, 62.4, 62.1, 61.8, 42.7, 42.5, 30.5, 30.3,
14.2, 13.8; IR (CHCl3) n 3031, 2987, 1741, 1718, 1556, 1375 cmꢁ1
;
HRMS (FAB+) calcd for [C14H18NO5]+: 280.1185, found:
280.1187; HPLC [Chiralcel AD-H, hexane/2-propanol ¼ 80/20,
Fig. 3 (a, b) Proposed transition state for asymmetric Michael addition 0.8 mL minꢁ1, l ¼ 210 nm] retention times: (major diaste-
using chiral (R,R)-1,2-diphenylethylenediamine-derived thiourea and
difference of relative free energy. (c, d) B3LYP/6-31G(d,p)-calculated
transition state of the DPEN-thiourea-catalyzed enantioselective
Michael reaction. Transition state structures for the C–C bond
formation, through which the main product (R) is possibly formed, are
also shown.
reomer) 10.0, 11.4 min, (minor diastereomer) 8.0, 19.9 min.
Ethyl 2-acetyl-2-methyl-4-nitro-3-phenylbutanoate (4b).
Colorless solid; mp 73–75 ꢀC; [a]2D0 ¼ ꢁ103.8 (c ¼ 0.0115,
1
CH2Cl2); H NMR (300 MHz, CDCl3) d 7.30–7.26 (m, 3H), 7.23–
7.20 (m, 2H), 4.95 (d, J ¼ 9 Hz, 2H), 4.23 (t, J ¼ 6 Hz, 1H), 4.14–
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4.08 (m, 1H), 4.07–4.01 (m, 1H), 2.12 (s, 3H), 1.43 (s, 3H), 1.20 (t, HPLC [Chiralcel AD-H, hexanes/2-propanol
¼
90/10, 0.5
J ¼ 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 205.6, 171.0, 135.6, mL minꢁ1, l ¼ 210 nm] retention times: (major enantiomer)
129.4, 128.9, 128.5, 76.9, 62.3, 62.1, 47.5, 27.8, 18.2, 14.0; IR 18.7 min, (minor enantiomer) 22.2 min, (minor diastereomers)
(CHCl3) n 3031, 1713, 1557 cmꢁ1; HRMS (FAB+) calcd for 17.3, 20.4 min.
[C15H20NO5]+: 294.1341, found: 294.1342; HPLC [Chiralcel OD-
Methyl
2-(2-nitro-1-phenylethyl)-1-oxo-2,3-dihydro-1H-
H, hexanes/2-propanol ¼ 90/10, 0.5 mL minꢁ1, l ¼ 210 nm] indene-2-carboxylate (4g).8,14a Yellow amorphous; [a]D20 ¼ ꢁ48.5
1
retention times: (major diastereomer) 21.4, 30.6 min, (minor (c ¼ 0.064, CH2Cl2); H NMR (300 MHz, CDCl3) d 7.77 (d, J ¼
diastereomers) 15.5, 19.2 min.
7.7 Hz, 0.57H), 7.68 (d, J ¼ 7.4 Hz, 0.43H), 7.58 (t, J ¼ 7.5 Hz,
Ethyl 1-(2-nitro-1-phenylethyl)-2-oxocyclopentanecarboxylate 0.43H), 7.51 (t, J ¼ 7.5 Hz, 0.57H), 7.42–7.32 (m, 1.43H), 7.29–
1
(4c). Colorless oil; [a]2D0 ¼ +10.7 (c ¼ 1.000, CH2Cl2); H NMR 7.07 (m, 5.57H), 5.43 (dd, J ¼ 3.9, 13.8 Hz, 0.43H), 5.24–5.14 (m,
(300 MHz, CDCl3) d 7.20–7.27 (m, 5H), 5.15–5.21 (dd, J ¼ 4.2 Hz, 1H), 5.06 (dd, J ¼ 3.6, 13.5 Hz, 0.57H), 4.48 (dd, J ¼ 3.5, 10.9 Hz,
3.9 Hz, 1H), 4.98–5.06 (dd, J ¼ 11.2 Hz, 11.0 Hz, 1H), 4.18–4.25 0.57H), 4.21 (dd, J ¼ 3.9, 11 Hz, 0.43H), 3.75 (s, 1.29H), 3.70 (s,
(m, 2H), 4.06–4.11 (dd, J ¼ 3.8 Hz, 3.8 Hz, 1H), 2.30–2.45 (m, 1.71H), 3.65 (d, J ¼ 17.9 Hz, 0.43H), 3.49 (d, J ¼ 17.6 Hz, 0.57H),
2H), 1.79–2.07 (m, 4H), 1.25–1.30 (t, J ¼ 7.2 Hz, 3H); 13C NMR 3.22 (d, J ¼ 14.3 Hz, 0.43H), 3.16 (d, J ¼ 14.3 Hz, 0.57H); 13C
(100 MHz, CDCl3) d 207.3, 169.8, 135.5, 129.6, 128.6, 128.4, 77.7, NMR (100 MHz, CDCl3) d 202.1, 200.1, 171.4, 170.1, 152.7, 152.6,
62.17, 47.9, 41.6, 37.2, 28.1, 22.5, 14.2; IR (CHCl3) n 3031, 2957, 136.3, 135.1, 135.0, 135.8, 134.9, 134.2, 129.26, 129.21, 129.03,
1751, 1727, 1556 cmꢁ1; HRMS (FAB+) calcd for [C16H20NO5]+: 128.8, 128.55, 128.52, 128.26, 128.23, 126.3, 125.3, 124.6, 77.6,
306.1341, found: 306.1341; major diastereomer: ee was deter- 77.03, 63.0, 61.9, 53.4, 47.7, 47.2, 36.76, 35.2; IR (CHCl3) n 3035,
mined by HPLC [Chiralpak OD-H column, hexanes/2-propanol 2955, 1739, 1711, 1607, 1556 cmꢁ1; HPLC [Chiralcel OD-H,
¼ 93/7, ow rate ¼ 1 mL minꢁ1, l ¼ 220 nm] retention times: hexanes/2-propanol ¼ 90/10, 1 mL minꢁ1, l ¼ 210 nm] reten-
(major enantiomer) 19.4 min, (minor enantiomer) 13.2 min, tion times: (major enantiomer) 42.1 min, (minor enantiomer)
(minor diastereomers) 11.3, 15.7 min.
Methyl 1-(2-nitro-1-phenylethyl)-2-
26.6 min, (minor diastereomers) 54.2, 34.4 min.
Methyl 1,2,3,4-tetrahydro-2-(2-nitro-1-phenylethyl)-1-
oxocyclopentanecarboxylate (4d). Colorless oil; [a]2D0 ¼ ꢁ152.9 oxonaphthalene-2-carboxylate (4h). Colorless solid; mp 101–
(c ¼ 0.045, CH2Cl2); 1H NMR (300 MHz, CDCl3) d 7.34–7.22 (m, 103 ꢀC; [a]D20 ¼ +51.0 (c ¼ 0.78, CHCl3); 1H NMR (300 MHz,
5H), 5.17 (dd, J ¼ 3.8, 13.5 Hz, 1H), 5.01 (dd, J ¼ 10.7, 13.5 Hz, CDCl3) d 8.04 (d, J ¼ 7.7 Hz, 1H), 7.50 (t, J ¼ 7.6 Hz, 1H), 7.41–
1H), 4.08 (dd, J ¼ 3.9, 10.8 Hz, 1H), 3.76 (s, 3H), 2.42–2.30 (m, 7.26 (m, 6H), 7.20 (d, J ¼ 7.7 Hz, 1H), 5.16 (dd, J ¼ 3.8, 13.5 Hz,
2H), 2.09–1.79 (m, 4H); 13C NMR for major diastereomer (100 1H), 5.05 (dd, J ¼ 10.1, 13.4 Hz, 1H), 4.21 (dd, J ¼ 3.8, 10.4 Hz,
MHz, CDCl3) d 212.5, 170.0, 135.4, 129.5, 129.0, 128.5, 76.6, 1H), 3.72 (s, 0.15H), 3.65 (s, 2.85H), 3.00–2.89 (m, 2H), 2.47–2.37
62.6, 53.2, 46.3, 38.1, 31.2, 19.5; IR (CHCl3) n 3031, 2957, 1751, (m, 1H), 2.10–1.99 (m, 1H); 13C NMR (100 MHz, CDCl3) d 194.4,
1727, 1556 cmꢁ1
;
HRMS (FAB+) calcd for [C15H19NO5]+: 170.4, 142.7, 136.1, 134.3, 131.7, 130.0, 128.9, 128.8, 128.6,
292.1185, found: 292.1180; HPLC [Chiralcel OD-H, hexanes/2- 128.4, 127.2, 78.0, 59.9, 52.9, 47.3, 30.9, 25.7; IR (CHCl3) n 3031,
propanol ¼ 93/7, 0.5 mL minꢁ1, l ¼ 210 nm] retention times: 2954, 1736, 1687, 1601, 1556 cmꢁ1; HRMS (FAB+) calcd for
(major enantiomer) 28.8 min, (minor enantiomer) 23.3 min, [C20H20NO5]+: 354.1341, found: 354.1345; HPLC [Chiralcel OD-
(minor diastereomers) 15.7, 18.5 min.
H, hexanes/2-propanol ¼ 90/10, 0.5 mL minꢁ1, l ¼ 254 nm]
Methyl
1-(2-nitro-1-phenylethyl)-2- retention times: (major enantiomer) 68.6 min, (minor enan-
oxocyclohexanecarboxylate (4e). Colorless solid; mp 100– tiomer) 14.7 min, (minor diastereomers) 17.0, 37.4 min.
20
1
ꢀ
102 C; [a]D ¼ +61.7 (c ¼ 0.018, CH2Cl2); H NMR (300 MHz,
Methyl
1-(2-nitro-1-p-tolylethyl)-2-
CDCl3) d 7.30–7.27 (m, 3H), 7.17–7.12 (m, 2H), 5.06 (dd, J ¼ 3.1, oxocyclopentanecarboxylate (4i). Colorless oil; [a]2D0 ¼ ꢁ156.1
1
13.5 Hz, 0.96H), 4.78 (dd, J ¼ 11.2, 13.2 Hz, 1H), 4.01 (dd, J ¼ 3, (c ¼ 0.049, CH2Cl2); H NMR (CDCl3, 300 MHz) 1.80–2.07 (m,
11.3 Hz, 0.96H), 3.75 (s, 2.88H), 3.68 (s, 0.12H), 2.57–2.39 (m, 4H), 2.30 (s, 3H), 2.35–2.42 (m, 2H), 3.75 (s, 3H), 4.05 (dd, J ¼
2H), 2.14–1.98 (m, 2H), 1.77–1.45 (m, 4H); 13C NMR (100 MHz, 4.1, 11 Hz, 1H), 4.98 (dd, J ¼ 10.7, 13.4 Hz, 1H), 5.13 (dd, J ¼ 4.1,
CDCl3) d 207.1, 170.3, 135.4, 129.5, 128.7, 128.4, 77.6, 63.2, 52.7, 13.7 Hz, 1H), 7.08–7.14 (m, 4H); 13C NMR (CDCl3, 100 MHz)
47.8, 41.6, 37.1, 28.1, 22.5; IR (CHCl3) n 3027, 2951, 1713, 212.5, 170.0, 138.2, 132.2, 129.7, 129.3, 76.6, 62.7, 53.2, 46.0,
1556 cmꢁ1; HRMS (FAB+) calcd for [C16H20NO5]+: 306.1341, 38.2, 31.2, 21.2, 19.5; IR (CH2Cl2) n 2967, 2935, 1760, 1613,
found: 306.1340; HPLC [Chiralcel OJ-H, hexanes/2-propanol ¼ 1556 cmꢁ1; HRMS (FAB+) calcd for [C16H20NO5]+: 306.1341,
80/20, 0.5 mL minꢁ1, l ¼ 210 nm] retention times: (major found: 306.1340; HPLC [Chiralcel OD-H, hexanes/2-propanol ¼
enantiomer) 50.8 min, (minor enantiomer) 45.6 min, (minor 97/3, ow rate ¼ 1 mL minꢁ1, l ¼ 220 nm] retention times:
diastereomers) 71.7, 94.4 min.
(major enantiomer) 25.1 min, (minor enantiomer) 16.4 min,
Methyl
1-(2-nitro-1-phenylethyl)-2- (minor diastereomers) 13.7, 18.0 min.
oxocycloheptanecarboxylate (4f).8,14a Colorless oil; [a]2D0
¼
Methyl
1-{1-(4-chlorophenyl)-2-nitro}ethyl-2-
+123.3 (c ¼ 0.025, CH2Cl2); H NMR (300 MHz, CDCl3) d 7.30– oxocyclopentanecarboxylate (4j). Colorless oil; [a]2D0 ¼ ꢁ135.8
1
1
7.25 (m, 3H), 7.17–7.10 (m, 2H), 4.99–4.89 (m, 2H), 4.07 (dd, J ¼ (c ¼ 0.052, CH2Cl2); H NMR (CDCl3, 300 MHz) 1.82–1.98 (m,
5, 9.1 Hz, 1H), 3.77 (s, 3H), 2.61–2.53 (m, 2H), 2.16–1.23 (m, 8H); 3H), 2.00–2.09 (m, 1H), 2.34–2.41 (m, 2H), 3.75 (s, 3H), 4.04 (dd,
13C NMR (100 MHz, CDCl3) d (major diastereomer) 208.4, 171.5, J ¼ 3.9, 14.9 Hz, 1H), 4.98 (dd, J ¼ 11.2, 13.7 Hz, 1H), 5.16 (dd, J
135.7, 129.5, 128.9, 128.5, 78.0, 65.7, 52.7, 48.7, 41.6, 33.1, 29.2, ¼ 3.8, 13.7 Hz, 1H), 7.13–7.29 (m, 4H); 13C NMR (CDCl3, 100
25.3, 24.7; IR (CDCl3) n 3030, 2938, 2863, 1736, 1709, 1556 cmꢁ1
;
MHz) 212.3, 169.9, 134.4, 134.1, 130.9, 129.1, 76.4, 62.4, 53.3,
31812 | RSC Adv., 2020, 10, 31808–31814
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45.7, 38.0, 31.4, 19.5; IR (CH2Cl2) n 2957, 2920, 2893, 1760, 23.4 min, (minor enantiomer) 17.1 min, (minor diastereomers)
1563 cmꢁ1; HRMS (FAB+) calcd for [C15H17ClNO5]+: 326.0795, 19.5, 20.5 min.
found: 326.0796; HPLC [Chiralcel OD-H, hexanes/2-propanol ¼
Methyl
1-(1-cyclohexyl-2-nitroethyl)-2-
97/3, ow rate ¼ 1 mL minꢁ1, l ¼ 220 nm] retention times: oxocyclopentanecarboxylate (4o).14d Colorless oil; [a]D20 ¼ ꢁ92.4
1
(major enantiomer) 42.5 min, (minor enantiomer) 28.3 min, (c ¼ 0.02, CH2Cl2); H NMR (CDCl3, 300 MHz) d 0.97–1.20 (m,
(minor diastereomers) 19.7, 23.7 min.
6H), 1.50–1.73 (m, 5H), 2.03–2.10 (m, 3H), 2.40–2.45 (m, 2H),
Methyl
1-{1-(4-bromophenyl)-2-nitroethyl}-2- 2.64–2.77 (m, 2H), 3.69 (s, 3H), 4.57 (dd, J ¼ 6.9, 15.1 Hz, 1H),
oxocyclopentanecarboxylate (4k). Colorless oil; [a]2D0 ¼ ꢁ99.4 5.09 (dd, J ¼ 3.8, 15.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
(c ¼ 0.058, CH2Cl2); 1H NMR (CDCl3, 300 MHz) d 1.85–1.99 (m, d 213.1, 170.1, 74.0, 62.2, 52.9, 45.2, 39.5, 38.0, 33.0, 32.4, 28.8,
4H), 2.34–2.44 (m, 2H), 3.75 (s, 3H), 4.03 (dd, J ¼ 3.9, 11 Hz, 1H), 27.0, 26.7, 26.0, 19.4; IR (CH2Cl2) n 2930, 2854, 1752, 1724,
4.98 (dd, J ¼ 11, 13.5 Hz, 1H), 5.16 (dd, J ¼ 3.8, 13.7 Hz, 1H), 1552 cmꢁ1; HPLC [Chiralcel OD-H, hexane/2-propanol ¼ 95/5,
7.13–7.29 (m, 4H); 13C NMR (CDCl3, 100 MHz) d 212.3, 169.9, ow rate ¼ 0.5 mL minꢁ1, l ¼ 215 nm] retention times:
134.4, 134.1, 130.9, 129.1, 76.4, 62.4, 53.3, 45.7, 38.0, 31.4, 19.5; (major enantiomer) 19.1 min, (minor enantiomer) 17.5 min,
IR (CH2Cl2) n 2956, 2920, 2892, 1754, 1562 cmꢁ1; HRMS (FAB+) (minor diastereomers) 12.2, 13.3 min.
calcd for [C15H17BrNO5]+: 370.0290, found: 370.0288; HPLC
Methyl
1-(3-methyl-1-nitrobutan-2-yl)-2-
[Chiralcel OD-H, hexanes/2-propanol ¼ 97/3, ow rate ¼ 1 oxocyclopentanecarboxylate (4p).14d Colorless oil; [a]2D0
¼
mL minꢁ1, l ¼ 220 nm] retention times: (major enantiomer) ꢁ152.3 (c ¼ 0.024, CH2Cl2); 1H NMR (CDCl3, 300 MHz) d 0.86 (d,
38.3 min, (minor enantiomer) 28.0 min, (minor diastereomers) J ¼ 6.9 Hz, 3H), 0.94 (d, J ¼ 6.9 Hz, 3H), 1.93–2.06 (m, 4H), 2.39–
21.5, 27.1 min.
2.44 (m, 2H), 2.70–2.74 (m, 1H), 2.79–2.83 (m, 1H), 3.70 (s, 3H),
Methyl
1-{1-(4-methoxyphenyl)-2-nitroethyl}-2- 4.51 (dd, J ¼ 6, 15.1 Hz, 1H), 5.15 (dd, J ¼ 4.1, 15.1 Hz, 1H); 13
C
oxocyclopentane-carboxylate (4l). Colorless oil; [a]D20 ¼ ꢁ177.6 NMR (CDCl3, 100 MHz) d 212.9, 169.9, 73.3, 62.3, 52.9, 45.5,
1
(c ¼ 0.05, CH2Cl2); H NMR (CDCl3, 300 MHz) d 1.79–2.05 (m, 38.1, 32.4, 28.9, 22.7, 19.4, 18.0; IR (CH2Cl2) n 2965, 1753, 1725,
4H), 2.31–2.43 (m, 2H), 3.75 (s, 3H), 3.77 (s, 3H), 4.06 (dd, J ¼ 1552 cmꢁ1; HPLC [Chiralcel OD-H, hexanes/2-propanol ¼ 95/5,
4.1, 11 Hz, 1H), 4.98 (dd, J ¼ 11, 13.2 Hz, 1H), 5.11 (dd, J ¼ 4.1, ow rate ¼ 1 mL minꢁ1, l ¼ 215 nm] retention times: (major
13.4 Hz, 1H), 6.83 (d, J ¼ 8.7 Hz, 2H), 7.17 (d, J ¼ 8.7 Hz, 2H); 13
C
enantiomer) 11.4 min, (minor enantiomer) 10.2 min, (minor
NMR (CDCl3, 100 MHz) d 212.6, 170.1, 159.5, 130.6, 127.1, 114.3, diastereomers) 19.3, 36.1 min.
76.7, 62.8, 55.3, 53.2, 45.7, 38.2, 31.1, 19.5; IR (CH2Cl2) n 2952,
Methyl
1-(2-nitro-1-p-tolylethyl)-2-
1711, 1553 cmꢁ1
;
HRMS (FAB+) calcd for [C16H19NO6]+: oxocyclohexanecarboxylate (4q). Slightly yellow oil; [a]2D0
¼
1
321.1212, found: 321.1210; HPLC [Chiralcel OD-H, hexanes/2- +351.0 (c ¼ 0.007, CH2Cl2); H NMR (300 MHz, CDCl3) d 7.10–
propanol ¼ 97/3, ow rate ¼ 1 mL minꢁ1, l ¼ 220 nm] reten- 7.07 (m, 2H), 7.01–6.99 (m, 2H), 5.05 (dd, J ¼ 3.3, 13.4 Hz, 1H),
tion times: (major enantiomer) 87.1 min, (minor enantiomer) 4.74 (dd, J ¼ 11.3, 13.2 Hz, 1H), 3.98 (dd, J ¼ 3, 11.3 Hz, 1H), 3.76
73.4 min, (minor diastereomers) 46.1, 57.4 min.
Methyl
(s, 3H), 2.53–2.43 (m, 2H), 2.30 (s, 3H), 2.11–1.99 (m, 2H), 1.73–
1-{1-(2-methoxyphenyl)-2-nitroethyl}-2- 1.46 (m, 4H); 13C NMR (100 MHz, CDCl3) d 207.2, 170.4, 138.2,
oxocyclopentane-carboxylate (4m). Colorless oil; [a]2D0 ¼ ꢁ17.3 132.2, 129.4, 129.3, 77.7, 63.2, 52.7, 47.4, 41.6, 37.1, 28.1, 22.5,
1
(c ¼ 0.04, CH2Cl2); H NMR (CDCl3, 300 MHz) d 1.83–2.04 (m, 21.2; IR (CH2Cl2) n 2950, 1743, 1712, 1554 cmꢁ1; LRMS (ESI)
4H), 2.32–2.42 (m, 2H), 3.75 (s, 3H), 3.80 (s, 3H), 4.33 (dd, J ¼ calcd for [C17H21NO5Na]+: 342.1317, found: 342.1297; HPLC
2.8, 9.9 Hz, 1H), 5.13 (dd, J ¼ 10.4, 13.7 Hz, 1H), 5.39 (dd, J ¼ 3.6, [Chiralcel OJ-H, hexane/2-propanol ¼ 80/20, 0.5 mL minꢁ1, l ¼
13.8 Hz, 1H), 6.86–6.93 (m, 2H), 7.23–7.27 (m, 2H); 13C NMR 210 nm] retention times: (major enantiomer) 41.9 min, (minor
(CDCl3, 100 MHz) d 231.1, 169.5, 157.8, 130.2, 129.6, 124.7, enantiomer) 25.8 min, (minor diastereomers) 23.8, 35.2 min.
121.2, 111.4, 76.8, 62.4, 55.7, 52.9, 38.0, 32.5, 19.2; IR (CH2Cl2) n
Methyl
1-{1-(4-chlorophenyl)-2-nitroethyl}-2-
2956, 2841, 1754, 1600, 1556 cmꢁ1; LRMS (ESI) calcd for oxocyclohexanecarboxylate (4r). Colorless oil; [a]D20 ¼ +61.7 (c
[C16H19NO6Na]+: 344.1110, found: 344.1137; HPLC [Chiralcel ¼ 0.018, CH2Cl2); H NMR (300 MHz, CDCl3) d 7.25–7.28 (m,
1
OJ-H, hexane/2-propanol ¼ 95/5, ow rate ¼ 1 mL minꢁ1, l ¼ 2H), 7.09–7.11 (m, 2H), 5.02 (dd, J ¼ 3.3, 13.4 Hz, 1H), 4.74 (dd, J
220 nm] retention times: (major enantiomer) 45.8 min, (minor ¼ 11.2, 13.4 Hz, 1H), 3.98 (dd, J ¼ 3, 11.3 Hz, 1H), 3.74 (s, 3H),
enantiomer) 51.6 min, (minor diastereomers) 54.3, 61.1 min.
2.50–2.44 (m, 2H), 2.13–2.00 (m, 2H), 1.75–1.47 (m, 4H); 13C
Methyl 1-(1-nitrohexan-2-yl)-2-oxocyclopentanecarboxylate NMR (100 MHz, CDCl3) d 206.9, 170.2, 134.3, 134.1, 130.9, 128.9,
(4n). Colorless oil; [a]2D0 ¼ ꢁ152.3 (c ¼ 0.024, CH2Cl2); 1H 77.4, 63.1, 52.8, 47.3, 41.6, 37.1, 28.0, 22.5; IR (CH2Cl2) n 2951,
NMR (CDCl3, 300 MHz) d 1.29–1.99 (m, 6H), 2.01–2.06 (m, 2H), 2868, 1712, 1554 cmꢁ1; LRMS (ESI) calcd for [C16H18ClNO5Na]+:
2.25–2.37 (m, 1H), 2.40–2.49 (m, 1H), 2.58–2.61 (m, 1H), 2.63– 362.0771, found: 362.0763; HPLC [Chiralcel OJ-H, hexanes/2-
2.85 (m, 1H), 3.71 (s, 3H), 4.38 (dd, J ¼ 5.5, 14 Hz, 1H), 4.88 (dd, J propanol ¼ 80/20, 0.5 mL minꢁ1, l ¼ 210 nm] retention
¼ 5, 14.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 213.51, 170.0, times: (major enantiomer) 31.2 min, (minor enantiomer)
76.5, 63.1, 53.0, 40.8, 38.4, 31.1, 30.1, 29.9, 22.7, 19.6, 14.0; IR 25.1 min.
(CH2Cl2) n 2957, 2841, 1751, 1726, 1553 cmꢁ1; LRMS (ESI) calcd
Methyl
1-{1-(4-bromophenyl)-2-nitroethyl}-2-
for [C13H21NO5Na]+: 294.1317, found: 294.1352; HPLC [Chir- oxocyclohexanecarboxylate (4s). Colorless oil; [a]D20 ¼ +61.7 (c
1
alcel OD-H, hexane/2-propanol
¼
95/5, ow rate ¼ 0.5 ¼ 0.018, CH2Cl2); H NMR (300 MHz, CDCl3) d 7.44–7.41 (m,
mL minꢁ1, l ¼ 215 nm] retention times: (major enantiomer) 2H), 7.05–7.02 (m, 2H), 5.02 (dd, J ¼ 3.3, 13.5 Hz, 1H), 4.74 (dd, J
¼ 11.2, 13.2 Hz, 1H), 3.97 (dd, J ¼ 3.3, 11.3 Hz, 1H), 3.74 (s, 3H),
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2.55–2.44 (m, 2H), 2.13–2.01 (m, 2H), 1.75–1.60 (m, 4H); 13C
NMR (100 MHz, CDCl3) d 206.9, 170.2, 134.6, 131.8, 131.3, 122.6,
77.3, 63.0, 52.9, 47.4, 41.6, 37.1, 28.0, 22.5; IR (CH2Cl2) n 2950,
1711, 1553 cmꢁ1; LRMS (ESI) calcd for [C16H18BrNO5Na]+:
406.0266, found: 408.0255; HPLC [Chiralcel OJ-H, hexane/2-
propanol ¼ 80/20, 0.5 mL minꢁ1, l ¼ 210 nm] retention
times: (major enantiomer) 40.5 min, (minor enantiomer)
37.1 min, (minor diastereomers) 17.7, 19.7 min.
Feuer and N. Ono, Wiley-VCH, 2001, DOI: 10.1002/
0471224480.ch6.
6 For reviews, see: (a) P. L. Dalko and L. Moisan, Angew. Chem.,
Int. Ed., 2004, 43, 5138; (b) J. Seayad and B. List, Org. Biomol.
Chem., 2005, 3, 719; (c) O. M. Berner, L. Tedeschi and
D. Enders, Eur. J. Org. Chem., 2002, 1877; (d) C. Grondal,
M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167; (e)
S. B. Tosgoeva, Eur. J. Org. Chem., 2007, 1701.
Methyl
1-{1-(4-methoxyphenyl)-2-nitroethyl}-2-
7 For recent papers on asymmetric organocatalytic Michael
reactions, see: (a) B. Tan, H. Torres and C. F. Barbas III,
Angew. Chem., Int. Ed., 2012, 51, 5381; (b) C. Curti,
G. Rassu, V. Zambrano, L. Pinna, G. Pelosi, A. Sartori,
L. Battisini, F. Zanardi and G. Casiraghi, Angew. Chem., Int.
Ed., 2012, 51, 6200; (c) P. Kwiatkowski and D. Lyzwa, Org.
Lett., 2011, 13, 3624; (d) G. Qing and S. L. You, Chem. Sci.,
2011, 2, 1519; (e) Y. Zhang, Y. Matsuo and E. Nakamura,
Org. Lett., 2011, 13, 6058.
8 T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.,
2003, 125, 12672.
9 T. Okino, Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto, J.
Am. Chem. Soc., 2005, 127, 119.
oxocyclohexane-carboxylate (4t). Slightly yellow oil; [a]D20
¼
+103.6 (c ¼ 0.01, CH2Cl2); 1H NMR (300 MHz, CDCl3) d 7.07–7.04
(m, 2H), 6.82–6.79 (m, 2H), 5.02 (dd, J ¼ 3.3, 13.2 Hz, 1H), 4.74
(dd, J ¼ 11.3, 12.9 Hz, 1H), 3.96 (dd, J ¼ 3, 11.3 Hz, 1H), 3.77 (s,
3H), 3.74 (s, 3H), 2.50–2.42 (m, 2H), 2.14–1.99 (m, 2H), 1.74–1.51
(m, 4H); 13C NMR (100 MHz, CDCl3) d 207.3, 170.4, 159.5, 130.6,
127.2, 114.0, 76.9, 63.4, 55.3, 52.7, 47.2, 41.6, 37.1, 28.1, 22.5; IR
(CH2Cl2) n 2952, 1711, 1553, 1514 cmꢁ1; LRMS (ESI) calcd for
[C17H21NO6Na]+: 358.1267, found: 358.1252; HPLC [Chiralcel
OJ-H, hexanes/2-propanol ¼ 80/20, 0.5 mL minꢁ1, l ¼ 210 nm]
retention times: (major enantiomer) 92.4 min, (minor enan-
tiomer) 76.7 min, (minor diastereomers) 46.1, 57.4 min.
10 A. Lattanzi, C. D. Fusco, A. Russo, A. Poater and L. Cavallo,
Chem. Commun., 2012, 48, 1650.
Conflicts of interest
11 (a) A. S. Paraskar and A. Sudalai, Tetrahedron, 2006, 62, 4907;
(b) S. Hajra, S. M. Aziz and R. Maji, RSC Adv., 2013, 3, 10185;
(c) D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald,
S. A. King, H. E. Morton, F. A. Plagge, M. Preskill,
S. H. Wagaw, S. J. Wittenberger and J. Zhang, J. Am. Chem.
Soc., 2002, 124, 13097; (d) T. Okino, Y. Hoashi,
T. Furukawa, X. Xu and Y. Takemoto, J. Am. Chem. Soc.,
2005, 127, 119; (e) J. Wang, W. Li, Y. Liu, Y. Chu, L. Lin,
X. Liu and X. Feng, Org. Lett., 2010, 12, 1280; (f)
K. L. Kimmel, J. D. Weaver, M. Lee and J. A. Ellman, J. Am.
Chem. Soc., 2012, 134, 9058.
There are no conicts to declare.
Acknowledgements
We are grateful for nancial support by Dr K. H. Kim. We
gratefully acknowledge the support from National Research
Foundation of Korea (NRF-2019R1814112), (NRF-2020R1C1C1-
013785). We thank Dr Yeonsun Hong for providing assistance.
Notes and references
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31814 | RSC Adv., 2020, 10, 31808–31814
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