Enantioselective synthesis of 4,5-disubstituted pyrrolidin-2-one derivatives with two stereocenters on the basis of Michael adducts

Article abstract of DOI:10.1007/s10593-020-02766-6

[Figure not available: see fulltext.] The addition of malonates to trans-β-alkyl-β-nitrostyrenes in the presence of chiral Mg²⁺ bisoxazoline complex and Ni²⁺ and Co²⁺ bis((S,S)- or (R,R)-N,N′-dibenzylcyclohexane-1,2-diamin

Full text of DOI:10.1007/s10593-020-02766-6

DOI 10.1007/s10593-020-02766-6
Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
Enantioselective synthesis of 4,5-disubstituted pyrrolidin-2-one derivatives
with two stereocenters on the basis of Michael adducts
Natalja Orlova1*, Maxim Vorona1, Vladislavs Baskevics1, Marina Petrova1,
Sergey Belyakov1, Helena Kazoka1, Ruslan Muhamadejev1, Grigory Veinberg1*
1 Latvian Institute of Organic Synthesis,
21 Aizkraukles St., Riga LV-1006, Latvia; e-mail: veinberg @osi.lv
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(8), 997–1009
Submitted February 3, 2020
Accepted after revision March 30, 2020
The addition of malonates to trans-β-alkyl-β-nitrostyrenes in the presence of chiral Mg2+ bisoxazoline complex and Ni2+ and Co2+
bis((S,S)- or (R,R)-N,N'-dibenzylcyclohexane-1,2-diamine) complexes resulted in the formation of Michael adducts with two stereo-
centers which were used as key precursors for the preparation of potentially biologically active enantiopure 4,5-disubstituted pyrrolidin-
2-one derivatives.
Keywords: chiral Mg2+, Ni2+, and Co2+ complexes, 4,5-disubstituted pyrrolidin-2-ones, Michael adduct, asymmetric catalysis.
According to structure–activity relationships, the biolo-
gical and pharmacological effectiveness of chiral γ-amino-
butyric acid (GABA) and its cyclic pyrrolidin-2-one
derivatives at the molecular level depends on the
configuration of substituents providing optimal interaction
with an appropriate receptor. Identification of stereoisomer
with such properties usually involves the development of
synthetic methodology suitable for the preparation of all
possible isomers and their comparable biological testing. It
explains the constant interest in the search for efficient
chiral catalysts for the preparation of chiral Michael
adducts and their subsequent conversion into biologically
active compounds.
were obtained by the resolution of racemic molecules or by
asymmetric synthesis in the presence of chiral catalysts.1–5
The addition of a vicinal chiral center to the carbon
skeleton of 2-pyrrolidinones 5–8 doubled the number of
possible chiral enantiomers. The synthetic problems that
arose during their preparation were also successfully solved
by the usage of chiral catalysts, resulting in the formation
of a pair of diastereoisomeric adducts usually as a mixture
of syn and anti isomers suitable for their conversion into
the target products.6–8 A similar approach was developed
for clausenamide 8 with three chiral centers in pyrrolidin-
2-one heterocycle.9
In general, the majority of published data devoted to this
problem have focused on the preparation of type I–IV
adducts with one or two chiral centers that were
successfully used as precursors in the preparation of mono-
or disubstituted linear or cyclic GABA analogs with
potential pharmaceutical application (Fig. 2).
The above-mentioned conditions fully apply to investi-
gations aimed at the synthesis of chiral drugs and biolo-
gically active compounds 1–8 on the basis of linear and
cyclic GABA derivatives (Fig. 1). In the case of drugs 1–4
with one chiral center, their individual R- or S-enantiomers
0009-3122/20/56(8)-0997©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
Figure 1. Chiral drugs and biologically active compounds on the basis of linear and cyclic GABA derivatives.
vicinally disubstituted enantiopure pyrrolidin-2-ones 14,
racetams 15, or GABA 16 according to a common retro-
synthetic design starting from nitroalkenes 9 or nitro-
alkanes 11 and malonic esters 10, 12 (Scheme 1), which
became the main purpose of the present research.
In accordance with the task described above, our efforts
were focused on the preparation of Michael adducts 13
(Table 1) with vicinal chiral centers in positions 1 and 2 of
the 2-nitroalkyl substituent with high ee values as a
potentially easily separable mixture of enantiomers with
syn or anti configuration suitable for conversion into four
individual enantiopure 4,5-disubstituted pyrrolidin-2-ones
14. In addition to the bis(oxazoline)Mg(OTf)2 complexes
Aa and Ab successfully employed for the preparation of
type I adducts and adopted from Barnes research,5a,7a the
following catalysts were also tested: (a) cinchona alkaloids
cupreine (Ba) and cupreidine (Bb) which demonstrated
excellent stereoselectivity in the case of unsubstituted
nitrostyrene and malonate;26 (b) Ni(II) bis((S,S)- or (R,R)-N,N'-
dibenzylcyclohexane-1,2-diamine) complexes C–E charac-
terized by high stereoselectivity in the case of nitrostyrene
unsubstituted in the position and malonate;10 (c) bis((R,R)-
N,N'-dibenzylcyclohexane-1,2-diamine) complexes F with
Figure 2. GABA precursors with one or two chiral centers.
According to the literature data, the catalysts used for
the preparation of the above-mentioned substances can be
divided into two categories: (1) complexes consisting of
chiral ligands and metal ions2,5a,6,10–14 and (2) chiral
thiourea, guanidine derivatives, or nitrogen-containing
heterocycles.3,15–25 Despite the large number of studies
carried out in the field of stereocontrolled Michael reactions
leading to the preparation of the adducts of type I–IV, the
possibilities of continued research in this direction are far
from exhausted, especially regarding the synthesis of type
IV compounds 13 and their further conversion into
Scheme 1. Retrosynthetic design leading to the stereocontrolled preparation of linear and cyclic disubstituted GABA derivatives
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Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
Table 1. Michael addition of malonates 10a,b to trans-β-alkyl-β-nitrostyrenes 9a,b in the presence of complexes Aa and Ab
Entry
Catalyst
Styrene
9a
Malonate
10a
R
R1
H
H
H
H
H
F
R2
Et
Time, days
Product
Yield*, %
ee**, %
90 (90)
90 (90)
80 (80)
86 (78)
84 (82)
70 (76)
94 (94)
–
syn/anti***
83/17 (80/20)
59/41 (60/40)
63/37 (63/37)
78/22 (68/32)
73/27 (73/27)
45/55 (48/52)
53/47 (50/50)
60/40
13a
1
2
Me
Me
Me
Et
7
7
7
7
7
4
4
1
1
1
81
–
Aa
Base*4
Ab
13a
13a
13b
13b
13c
13c
13a
13b
13c
Et
9a
10a
3
Et
79
71
72
63
51
78
69
78
9a
10a
4
Et
Aa
9b
10a
5
Et
Et
Ab
9b
10a
6
Me
Me
Me
Et
Me
Me
Et
Aa
9a
10b
7
F
Ab
9a
10b
8
TMG
TMG
TMG
H
H
F
9a
10a
9
Et
–
65/35
9b
10a
10
Me
Me
–
50/50
9a
10b
* Adducts were prepared in CHCl3 (50 ml) containing malonate 9 (2.5 mmol), nitrostyrene 10 (2.5 mmol) in the presence of 30 mol % of catalyst,
morpholine (12 ml, 0.14 mmol), and tetramethylguanidine (TMG) (12 ml, 0.09 mmol) at room temperature for 4–7 days. The evaluation of the content of
individual diastereomers and enantiomers in adducts was performed on the basis of chiral HPLC retention time data after chromatographic purification of
reaction product.
** ee Values for syn and anti (in brackets) diastereomers were calculated on the basis of HPLC data for the (1R,2S)/(1S,2R) and (1R,2R)/(1S,2S) pairs of
enantiomers in accordance with the chirality of catalysts Aa and Ab.
*** syn/anti Diastereomeric ratios for the major and minor (in brackets) enantiomers were calculated on the basis of HPLC data for the integrated
concentrations of the 1R,2S- and 1R,2R- or 1S,2R- and 1S,2S-stereoisomers in accordance with the chirality of catalysts Aa and Ab.
*4 Chiral adduct 13a (entry 1) after isolation was additionally treated by TMG at room temperature for 7 days.
Zn2+, Mg2+, Cu2+, Fe3+, Ba2+, or Co2+ ions and (d) Co(II)
bis((S,S)-N,N'-dibenzylcyclohexane-1,2-diamine) complex G
(Fig. 3).
a similar excess of syn stereoisomer (1S,3R)-13b was also
obtained after the conjugated addition of nitropropane to
benzylidenemalonate catalyzed by chiral N-spiro
ammonium bromides.25a
The preferred formation of syn enantiomers 13a,b with
1R,2S- or 1S,2R-configuration was also proved by the
X-ray structural analysis of compound (1R,2S)-13a (Fig. 4).
Similar tendency in the syn/anti ratio were observed even
in the case of racemic compounds 13a,b (entries 8, 9).
In addition to our previous research,7a it was found that
complexes Aa and Ab provided high ee values for all four
stereoisomers of adducts 13a–c obtained by the conjugated
addition of malonate 10a not only to β-methyl-
β-nitrostyrene 9a (Table 1, entries 1–3), but also to its
homolog 9b (entries 4 and 5). According to literature data,
Figure 3. Chiral catalysts tested in the preparation of Michael adducts from nitroalkenes and malonates.
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Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
isomer well agreed with the calculated dihedral angles of
ϕ1 = –169.62° and ϕ2 = 164.99° in the appropriate
conformer (Fig. 5). The calculated difference in free
energies for the optimized conformers was positive and
equal to 1.15 kcal/mol proving higher stability of com-
pound syn-(1R,2S)-13b.
The gauche conformation for the vicinal protons at C-1
and C-2 stereocenters in compound 13a could be partially
changed in the favor of stereoisomers with an anti orienta-
tion. This effect was achieved by the treatment of the
sample of compound 13a obtained according to the proce-
dure described in Table 1, entry 1, at room temperature in
CHCl3 for several days in the presence of a deprotonating agent
such as a tetramethylguanidine (TMG) (Table 1, entry 2). It
reduced the concentration of syn isomer (1R,2S)-13a by up
to 23% in favor of anti isomer (1R,2R)-13a reaching the
same syn/anti ratio as in the racemic mixture (entry 8) and
with practically unchanged ee values in the beginning and
the end of the experiment.
An increase in the concentration of the anti isomer
observed in the experiments using styrene 9b (Table 1,
entries 4, 5, 9) and especially malonate 10b (entries 6, 7,
10) indicated various possibilities to regulate the stereo-
chemistry of C-2 atom in adducts 13a–c.
However, the usage of this method is not very promising
for the large-scale production of adducts due to the high
concentration of catalysts Aa or Ab and a multiday
duration of the reaction preferably at room temperature.
In continuation of the study, we applied cupreine (Ba)
and cupreidine (Bb) catalysts which had been successfully
used for the asymmetric preparation of type I Michael
adducts.26 Low ee values for stereoisomeric adducts 13a
presented in Scheme 2 demonstrated only moderate
effectiveness of these catalysts.
Figure 4. Molecular structure of compound (1R,2S)-13a with
atoms representad as thermal vibration ellipsoids of 50%
probability.
The higher stability of compound syn-(1R,2S)-13b,
which has gauche conformation for the vicinal protons
EtCH–CHPh, in comparison with its anti-(1S,2R)-13b
isomer was proved using theoretical calculations of the
potential energy surfaces (PES). In the case of compound
syn-(1R,2S)-13b the two protons were characterized by a
dihedral angle of ϕ1 = 64.94°. At the same time, the dihedral
angle ϕ2 between the vicinal protons PhCH–CH(COOEt)2
was equal to 173.08° (Fig. 5). According to X-ray analysis
data, molecule syn-(1R,2S)-13a is characterized with
similar dihedral angles: ϕ1 = 64.94° and ϕ2 = 173.08°.
Considerably better catalytic activity was demonstrated
by chiral Ni(II) bis((R,R)- or (S,S)-N,N'-dibenzylcyclo-
hexane-1,2-diamine) complexes C, Da,b, and E (Fig. 3)
originally developed by Evans for the preparation of type I
adducts.10 According to the data presented in Table 2, the
In contrast, anti conformation of vicinal protons EtCH–
CHPh and PhCH–CH(COOEt)2 in compound (1R,2R)-13b
Figure 5. Calculated structure and dihedral angles for (1R,2S)-13b and (1R,2R)-13b conformers (Table 1, entry 4).
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Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
Scheme 2. Michael addition of malonate 10a to trans-β-methyl-β-nitrostyrene (9a) in the presence of cupreine (Ba) and cupreidine (Bb)
Table 2. Michael addition of malonate 10c to trans-β-alkyl-β-nitrostyrenes 9a–c in the presence of Ni2+ complexes C, Da,b, E
Entry Catalyst* Styrene
Ar
R
Temperature, °C
Time, h
Product
Yield, % *
ee**, %
syn/anti***
1
2
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
55
20
55
55
55
55
55
100
100
55
55
55
55
55
55
20
20
20
48
144
72
72
72
72
72
18
18
36
36
48
72
72
72
24
24
24
13d
13d
13d
13d
13d
13d
13d
13d
13d
13d
13d
13e
13e
13f
54
46
85
83
62
84
58
87
86
95
94
45
75
74
80
78
69
78
90 (88)
88 (88)
86 (90)
90 (94)
84 (78)
90 (88)
84 (77)
76 (82)
82 (86)
84 (84)
88 (88)
80 (86)
82 (82)
88 (84)
88 (90)
–
72/28 (69/31)
70/30 (71/29)
89/11 (84/16)
71/29 (79/21)
53/47 (45/55)
56/44 (51/49)
56/44 (48/52)
60/40 (68/32)
62/38 (69/31)
58/42 (60/40)
64/36 (75/25)
58/42 (64/36)
62/38 (56/44)
58/42 (48/52)
60/40 (65/35)
51/49
C
Da
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
9b
9c
9c
9a
9b
9c
3
Ph
C
4
Ph
Da
5
Ph
E
6
Ph
Da
Db*4
7
Ph
8
Ph
C
9
Ph
Da
10
11
12
13
14
15
16
17
18
C*5
Da*5
C
Ph
Ph
Ph
Ph
Et
Da
4-FC6H4
4-FC6H4
Ph
Me
Me
Me
Et
C
13f
Da
13d
13e
13f
TMG
TMG
TMG
Ph
–
54/46
4-FC6H4
Me
–
60/40
* Reactions were performed in PhMe (10 ml) containing nitrostyrene 9a–c (1.0 mmol), malonate 10c (1.0 mmol), and Ni(II)-complex C, Da,b, E (6 mol %) in a
screw cup vial at room or up to 100°C temperature controlling adduct formation by LC/MS analysis. The evaluation of the content of individual diastereo-
mers and enantiomers in adducts was performed on the basis of chiral HPLC retention time data after chromatographic purification of reaction product.
** ee Values for syn and anti (in brackets) diastereomers were calculated as described for Table 1.
*** syn/anti Diastereomeric ratios for the major and minor (in brackets) enantiomers were calculated as described for Table 1.
*4 Catalyst preparation was realized in situ directly in the reaction mixture.
*5 Reaction was carried out in the absence of solvent.
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Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
Table 3. Michael addition of malonate 10c to trans-β-alkyl-β-nitrostyrene (9a) in the presence
of bis((R,R)-N,N'-dibenzylcyclohexane-1,2-diamine) complexes with metal ions Fa–k*
Entry
Catalyst
Metal
X
Yield of compound 13d, %
ee**, %
syn/anti***
1
2
Zn2+
Zn2+
Zn2+
Zn2+
Mg2+
Mg2+
Cu2+
Fe3+
OAc
OTf
Cl
36
38
28
17
82
91
33
30
26
88
81
8 (24)
64 (52)
4 (0)
75/25 (67/33)
60/40 (72/28)
48/52 (63/37)
55/45 (57/43)
80/20 (87/13)
71/29 (73/27)
67/33 (67/33)
60/40 (61/39)
67/33 (67/33)
64/36 (66/64)
60/40 (55/45)
Fa
Fb
Fc
Fd
Fe
Ff
3
4
Br
4 (0)
5
OTf
Cl
54 (70)
36 (40)
58 (60)
4 (2)
6
7
OTf
OAc
Cl
Fg
Fha
Fi
8
9
Ba2+
Co2+
Co2+
6 (6)
10
11
Cl
84 (84)
80 (78)
Fj
OAc
Fk
* Reactions were performed in PhMe (10 ml) containing nitrostyrene 9a (1.0 mmol), malonate 10c (1.0 mmol) using catalysts Fa–k (6 mol %) in a screw
cup vial at 44°C controlling adduct formation by LC/MS analysis. Identification and quantitative evaluation of individual enantiomers in adducts 13d was
realized on the basis of chiral HPLC retention time data.
** ee Values for syn and anti (in brackets) diastereomers were calculated as described for Table 1.
*** syn/anti Diastereomeric ratios for the major and minor (in brackets) enantiomers were calculated as described for Table 1.
effectiveness of these complexes could be successfully
extended to the preparation of adducts with two vicinal
stereocenters with high ee values and increased diastereo-
selectivity toward the formation of anti isomers.
cyclohexane-1,2-diamine ligands was prepared. Its X-ray
analysis data (Fig. 6) demonstrated a trans-equatorial
coordination of ligands with two H2O molecules in apical
positions, one of which was connected by hydrogen bonds
with two bromine ions. The ee and syn/anti ratios values of
stereoisomeric adducts 13d prepared in the presence of
compound G and presented in the Table 4 were similar
to those demonstrated by catalyst C (Table 2, entries 1,
12, 14).
In addition, catalysts C, Da,b, and E preserved the
important catalytic advantages developed in the Evans
study such as relatively low catalyst loading (6 mol %),
effectiveness in the absence of base and at elevated
temperatures up to 100°C (Table 2, entries 8, 9). Moreover,
the formation of type IV adducts with moderate results
took place even in the absence of solvent (entries 10, 11).
In the case of Ni(OAc)2, its interaction with the ligand
leading to the formation of catalytic complex Db was
achieved in situ in a reaction mixture at 55°C (entry 7). The
usage of β-nitrostyrenes 9b,c modified in the β-position or
aromatic ring resulted in the formation of adducts with
similar characteristics.
The catalytic effectiveness of complexes C, Da,b, and E
based on chiral N,N'-dibenzylcyclohexane-1,2-diamine
ligands prompted us to explore the catalytic properties of
the same ligand complexed with other metal ions. The data
in Table 3 demonstrate the low catalytic efficiency or lack
of it in the case of complexes Fa–k containing Zn2+, Mg2+,
Fe3+, Cu2+, or Ba2+ ions. The only positive result was
obtained in the presence of Co2+ complexes Fj,k (Table 3,
entries 10 and 11). Similar catalytic properties for this ion
were described for bis(imidazolidine)pyridine–CoCl2
complex in 2019.27
Figure 6. Molecular structure of cobalt(II) bis((S,S)-N,N'-dibenzyl-
cyclohexane-1,2-diamine) complex G with atoms representad as
thermal vibration ellipsoids of 50% probability.
In the continuation of this research, crystalline catalyst
G on the basis CoBr2 and two chiral (S,S)-N,N'-dibenzyl-
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Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
Table 4. Michael addition of malonate 10c to trans-β-alkyl-β-nitrostyrenes 9a–c in the presence
of a Co(II) bis((S,S)- N,N'-dibenzylcyclohexan-1,2-diamine) complex G*
Entry
Styrene
R
Ph
R1
Me
Me
Me
Et
Solvent
Me2CO
PhMe
Product
13d
Yield, %
ee**, %
90 (62)
82 (90)
84 (52)
82 (86)
78 (70)
syn/anti***
65/35 (29/71)
60/40 (76/24)
66/34 (34/66)
60/40 (65/35)
58/42 (50/50)
1
2
3
4
5
86
84
81
78
85
9a
9a
9a
9b
9c
13d
Ph
13d
13e
13f
Ph
EtOAc
PhMe
Ph
4-FC6H4
Me
PhMe
* Reactions were performed in PhMe (10 ml) containing nitrostyrene 9a–c (1.0 mmol), malonate 10c (1.0 mmol) using catalyst G (6 mol %) in a screw
cup vial for 24 h at 45°C controlling adduct formation by LC/MS analysis. The evaluation of the content of individual diastereomers and enantiomers in
adducts was performed on the basis of chiral HPLC retention time data after chromatographic purification of reaction product.
** ee Values for syn and anti (in brackets) diastereomers were calculated as described for Table 1.
*** syn/anti Diastereomeric ratios for the major and minor (in brackets) enantiomers were calculated as described for Table 1.
The stereocontrolled preparation of new Michael
adducts 13e,f with two stereocenters in the C-1 and C-2
positions catalyzed by Ni(II) complexes C and Da allowed
to transform them into four enantiopure 4,5-disubstituted
pyrrolidin-2-ones 14a,b using methodology developed in
our previous study.7a It included: (a) hydrolysis and
decarboxylation of enantiomerically enriched diastereomer
mixtures (1R,2S)/(1R,2R) and (1S,2R)/(1S,2S) of the
respective compounds 13e,f into intermediate 4-nitro-
butanoic acids followed by their conversion into appro-
priate methyl esters: (1R,2S)/(1R,2R)- and (1S,2R)/(1S,2S)-
17a,b; (b) chromatographic separation of syn and anti
diastereoisomers; (c) reduction and cyclization of
individual methyl 4-nitrobutanoates (3R,4S)-, (3R,4R)-,
(3S,4R)-, and (3S,4S)-17a,b into 4,5-disubstituted pyrro-
lidin-2-ones (4R,5S)-, (4R,5R)-, (4S,5R)-, and (4S,4S)-14a,b
(Scheme 3). The corresponding racemic compounds 14a,b
have been described previously.28
Experimental realization of decarboxylation and reeste-
rification processes (Scheme 3) in rather aggressive condi-
tions created a risk of the racemization of intermediates
17e,f and, accordingly, final products 14a,b. However, the
comparison of ee and syn/anti ratio data for the starting
stereoisomeric mixtures (1R,2S)/(1R,2R)-13e and (1S,2R)/
(1S,2S)-13e and four final products (4R,5S)-, (4R,5R)-,
(4S,5R)-, and (4S,4S)-14a (Table 5) demonstrated retention
of chiral stability during the whole process.
The presented study offers comparative analysis of the
catalytic effectiveness of already known and new chiral
catalysts in the preparation of Michael adducts with two
vicinal stereocenters. The most promising were chiral Mg(II)
bis(oxazoline)2 complex, as well as Ni(II) or Co(II) bis((S,S)-
Scheme 3. Conversion of adducts 13e,f into enantiopure 3,4-disubstituted pyrrolidin-2-ones 14a,b
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Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
Table 5. Enantiomeric excess (ee) ratio of pyrrolidin-2-ones 14a in comparison with the corresponding starting nitro adducts 13e
Adducts 13e*
ee**, %
syn/anti***
Pyrrolidin-2-ones
ee**, %
cis/trans***
(1R,2S)/(1R,2R)-13e
80 (80)
58/42
cis-(4R,5S)-14a
trans-(4R,5R)-14a
cis-(4S,5R)-14a
trans-(4S,4S)-14a
83 (84)
88 (86)
82 (82)
90 (82)
90/10
6/94
91/9
7/93
(1S,2R)/(1S,2S)-13e
82 (82)
62/38
* Table 2, entries 12, 13.
** ee Values for major and minor (in brackets) diastereomers.
*** Data for the major enantiomer only.
or (R,R)-N,N'-dibenzylcyclohexane-1,2-diamine) complexes,
which were successfully employed in the preparation of
adducts with fixed configuration of C-1 and variable one of
C-2 chiral center. In addition, the adducts thus obtained
were successfully converted into enantiopure 4,5-disub-
stitued pyrrolidin-2-ones useful as key intermediates in the
preparation and biological testing of appropriate racetams
or GABA derivatives.
Merck 60 F254 silica gel plates. Merck Kieselgel silica gel
(0.063–0.230 mm) was used for column chromatography.
Cupreidine (Bb) was supplied by Toronto Research
Chemicals. All other chemicals were supplied by Sigma-Aldrich.
Stereochemical assignements. The absolute configu-
ration for diethyl (1R,2S)-, (1R,2R)-, (1S,2R)-, and (1S,2S)-
2-(2-nitro-1-phenylpropyl)malonates 13a was confirmed by
their chemical conversion into enantiopure 2-(5-methyl-
4-phenyl-2-oxopyrrolidin-1-yl)acetamides.7a The absolute
configurations of their structural analogs 13b–f were
assigned by analogy on the basis of their HPLC data.
(3aR,8aS,3a'R,8a'S)-2,2'-Сyclopropane-1,1-diylbis-
(8,8a-dihydro-3aH-indeno[1,2-d]oxazole)magnesium(II)
triflate (Aa) and (3aS,8aR,3a'S,8a'R)-2,2'-cyclopropane-
1,1-diylbis(8,8a-dihydro-3aH-indeno[1,2-d]oxazole)magne-
sium(II) triflate (Ab) were prepared according to literature
method.5a
Bis((S,S)-N,N'-dibenzylcyclohexane-1,2-diamine)-
nickel(II) bromide (C), bis((R,R)-N,N'-dibenzylcyclo-
hexane-1,2-diamine)nickel(II) bromide (Da), bis((R,R)-
N,N'-dibenzylcyclohexane-1,2-diamine)nickel(II) acetate
(Db), and ((S,S)-N,N'-dibenzylcyclohexane-1,2-diamine)-
nickel(II) acetate (E) were prepared according to literature
method.10
Experimental
The IR spectra were recorded on a Shimadzu IRPrestige-21
Fourier transform infrared spectrophotometer in thin films.
1
The one-dimensional H, 13C, and 19F NMR spectra (400,
100, and 376 MHz, respectively) and two-dimensional
NOESY, 1H–13C HMBC, 1H–13C HSQC spectra were
recorded on a Varian Mercury 400 instrument in CDCl3 at
25°C. The chemical shifts of the hydrogen and carbon
atoms are referred to the residual signals of CDCl3 1at 7.26
(1H) and 77.0 (13C) ppm, respectively. Complete H and
13C NMR signal assignments and the identification of
stereochemistry of pairs of diastereomers were made by
homonuclear and heteronuclear 2D NMR experiments with
1
the special attention to homonuclear H–1H and hetero-
1
nuclear H–13C coupling constants. The 19F NMR signals
were indirectly referenced to CFCl3. LC/MS analysis data
were obtained using a Waters Acquity UPLC system with a
photodiode array detector, Acquity UPLC BEH C18 1.7 µm
2.1 × 50 mm column, and a Waters SQ2 mass spectrometer
with single quadrupole detector and electrospray ioniza-
tion. High-resolution mass spectra were recorded on a
Micromass Quatro Micro™ instrument with electrospray
ionization. The melting points were determined using a
Boetius PNMK melting point apparatus and are reported
uncorrected. Optical rotation measurement was performed
on an automated Rudolf Research Analytical Polarimeter
Autopol IV. Chiral HPLC measurements were performed
on a Waters Alliance LC system equipped with 2695
separation module, quaternary pump, degasser, auto-
sampler, column thermostat, and a Waters 2489 double-
absorbed UV detector (employed at 210 nm wavelength)
using a Chiralpak IA column (4.6 mm × 250 mm, 5 µm),
and the output signal was monitored and processed using
the Waters Empower 2 software; the enantiomeric elution
order and the assignment of HPLC peaks were established
by the usage of racemic adducts as external standards,
Zn(II), Mg(II), Cu(II), Fe(II), Ba(II), and Co(II) comp-
lexes with (R,R)-N,N'-dibenzylcyclohexane-1,2-diamine
Fa–k. A mixture of the appropriate metal salt (2 mmol) and
(R,R)-N,N'-dibenzylcyclohexane-1,2-diamine (1177 mg,
4.0 mmol) in MeCN (50 ml) was heated at reflux for 5 h.
Reaction mixture was cooled and evaporated under reduced
pressure. The residue was dissolved in CH2Cl2 and filtered.
The solvent from the filtrate was evaporated under reduced
pressure to obtain the crude product used in experiments
without additional purification.
Diaquabis((S,S)-N,N'-dibenzylcyclohexane-1,2-diamine)-
cobalt(II) dibromide tetrahydrate (G). A mixture of
CoBr2 (437 mg, 2 mmol) and (S,S)-N,N'-dibenzylcyclo-
hexane-1,2-diamine (1177 mg, 4.0 mmol) in MeCN
(50 ml) was heated at reflux for 5 h. Reaction mixture was
cooled and evaporated under reduced pressure, and the
crude product was recrystallized from a mixture of EtOAc
and 96% EtOH. Yield 1116 mg (80%), microcrystalline
pale-green powder. [α]20D +63° (c 0.87, CH2Cl2). IR spectrum,
ν, cm–1: 3254, 3142, 3028, 2933, 2859, 1496, 1453, 1353,
1029, 948, 752, 700.
1
X-ray crystallographic and H NMR analysis data. The
Addition of nitrostyrenes 9a,b to malonates 10a,b in the
presence of chiral catalysts Aa or Ab (General method I).
purity of the compounds was determined by TLC using
1004

Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
Mg(OTf)2 (160 mg, 0.5 mmol) and H2O (13 l) were added
Preparation of enantiopure 3,4-disubstituted methyl
4-nitrobutanoates 17a,b (General method VI). The
appropriate diastereoisomeric mixture of adduct 13e,f
(1.8 mmol) was hydrolized and decarboxylated in a
refluxing mixture of 36% aqueous HCl and AcOH in the
ratio of 1:3 (30 ml) for 18 h. After the completion of the
reaction, the solution was cooled and concentrated under
reduced pressure. The residue was purified by column
chromatography using as eluent petroleum ether – EtOAc,
5:1. Isolated mixtures of syn and anti isomers of the
respective intermediate 3,4-disubstituted 4-nitrobutanoic
acids were dissolved in SOCl2 (0.12 g, 1.0 mmol) and
MeOH (20 ml) mixture and refluxed for 20 h. The reaction
mixture was cooled and concentrated under reduced
pressure. Syn and anti isomers were separated by column
chromatography using as eluent petroleum ether – EtOAc,
5:1.
Preparation of enantiopure 4,5-disubstituted pyrroldin-
2-ones 14a,b (General method VII). Enantiopure samples
of methyl 4-nitrobutanoates 17a,b (2.2 mmol) were
hydrogenated in EtOH (40 ml) in the presence of 50%
Raney Ni slurry in H2O (1 ml) at 10 bar at 40°C for 20 h.
After the completion of the reaction, the reaction mixture
was cooled, and the catalyst was filtered off and washed
with EtOH (30 ml). The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography using as eluent CH2Cl2–EtOH,
20:1.
Diethyl 2-((1R,2S)- and (1R,2R)-2-nitro-1-phenyl-
propyl)malonate ((1R,2S)- and (1S,2S)-13a) and diethyl
(1S,2R)- and (1S,2S)-2-(2-nitro-1-phenylpropyl)malonate
((1S,2R)- and (1S,2S)-13a)7a were prepared from
nitrostyrene 9a and malonate 10a according to the general
method I or II. Recrystallization of the isolated product
from EtOAc–hexane mixture allowed to obtain colorless
crystals of compound (1R,2S)-13a, mp 51–53°C, characte-
rized by X-ray crystallography (Fig. 4).
Epimerization of compound (1R,2S)- and (1S,2S)-13a.
The mixture of stereoisomers of compound (1R,2S)- and
(1S,2S)-13a (50 mg, 0.15 mmol), prepared according to the
general method I, and TMG (6 l, 0.05 mmol) in CHCl3
(5 ml) was stirred at room temperature for 7 days. The
reaction mixture was concentrated under reduced pressure,
and the residue was dissolved in CH2Cl2 (20 ml). The
obtained solution was washed with 5% aqueous HCl
(2×20 ml) and brine (2×50 ml), and the organic phase was
dried over anhydrous Na2SO4. The drying reagent was
removed by filtration, the solution was concentrated under
reduced pressure, and the crude product underwent chiral
HPLC analysis.
to a solution of (3aR,3'aR,8aS,8'aS)-2,2'-cyclopropylidene-
bis[3a,8a]dihydro-8H-indeno[1,2-d]oxazole or (3aS,3'aS,8aR,8'aR)-
2,2'-cyclopropylidenebis[3a,8a]dihydro-8H-indeno[1,2-d]-
oxazole (267 mg, 0.75 mmol) in CHCl3 (amylene-stabi-
lized) (5 ml) in a 250-ml reaction flask at room tempe-
rature. The mixture was stirred under argon for 1 h. Mole-
cular sieves (1.0 g) were added to the mixture, and the
mixture was stirred for additional 30 min. A solution of
malonate 9a,b (2.5 mmol), nitrostyrene 10a,b (2.5 mmol),
morpholine (12 l, 0.14 mmol), and TMG (12 l,
0.09 mmol) in CHCl3 (45 ml) was added to the obtained
suspension. The reaction mixture was stirred at room
temperature 4–7 days while monitoring the progress of
reaction by LC/MS. After the completion of the reaction,
the reaction mixture was concentrated under reduced pressure.
The crude product was purified by column chromatography
using as eluent petroleum ether – EtOAc, 5:1.
The addition of nitrostyrene 9a to malonate 10a in the
presence of chiral catalysts Ba or Bb (General method II).
A solution of malonate 9a (0.67 mmol), nitrostyrene 10a
(0.67 mmol), and 4-[(R)-((2S,4S,5R)-5-ethenyl-1-azabicyclo-
[2.2.2]octan-2-yl)(hydroxy)methyl]quinolin-6-ol (cupreine,
Ba) or 4-[(S)-((2R,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]-
oct-2-yl)(hydroxy)methyl]quinolin-6-ol (cupreidine, Bb)
(21 mg, 0.067 mmol) in dry THF (8 ml) under N2
atmosphere was stirred at room temperature for 2 days
while monitoring the reaction by LC/MS. After the
completion of the reaction, the reaction mixture was
concentrated under reduced pressure and the crude product
was purified by column chromatography using as eluent
petroleum ether – EtOAc, 5:1.
The addition of nitrostyrenes 9a–c to malonates 10c in
the presence of chiral catalysts C–E (General method III).
Nitrostyrene 9a–c (1.0 mmol), malonate 10c (1.0 mmol),
and 6 mol % of Ni(II)-complexes C, Da,b, or E in PhMe
(5 ml) or neat were placed in a screw cup vial and stirred at
chosen temperature (Table 2) while controlling product
formation by LC/MS. After the completion of the reaction,
the reaction mixture was concentrated under reduced
pressure and the crude product was purified by column
chromatography using as eluent petroleum ether – EtOAc,
5:1. In the case of catalyst Db, it was formed in situ by the
addition Ni(OAc)2 (4 mg, 0.0012 mmol) and (S,S)-N,N'-
dibenzylcyclohexane-1,2-diamine (14 mg, 0.0024 mmol)
into the reaction mixture of nitrostyrene 9a (65 mg, 0.4 mmol)
and malonate 10c (52.8 mg, 0.4 mmol) in PhMe (5 ml).
The addition of nitrostyrene 9c to malonates 10c in
the presence of chiral complexes Fa–k and G (General
method IV) was performed at 44°C for 24 h using PhMe (10 ml)
as solvent following general method III in all other details.
Preparation of racemic Michael adducts 13a–f (General
method V). A solution of nitrostyrene 9a–c (3.1 mmol),
malonate 10a–c (3.1 mmol), and TMG (0.31 mmol) in
CHCl3 (20 ml) was stirred at 20°C for 24 h estimating the
degree of conversion by TLC. After the completion of the
reaction, the reaction mixture was concentrated under
reduced pressure and the crude product was purified by column
chromatography (eluent petroleum ether – EtOAc, 5:1).
Diethyl (1R,2S)- and (1R,2R)-2-(2-nitro-1-phenylbutyl)-
malonate ((1R,2S)- and (1R,2R)-13b) was prepared in the
presence of catalyst Aa according to the general method I
from nitrostyrene 9b and malonate 10a. Yield 0.60 g
(71%), low melting solid. IR spectrum, ν, cm–1: 2981,
2940, 1751, 1734, 1550, 1369. Found, m/z: 360.1418
[M+Na]+. C17H23NNaO6. Calculated, m/z: 360.1418.
1
Compound syn-(1R,2S/1S,2R)-13b. H NMR spectrum,
δ, ppm (J, Hz): 7.23–7.20 (3H, m, H Ph); 7.05–7.01 (2H,
1005

Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
m, H Ph); 4.93–4.87 (1H, m, CH); 4.26–4.18 (2H, m, CH2);
4.14 (2H, q, J = 7.1, CH2); 4.03 (1H, d, J = 10.9, CH); 3.85–
3.75 (1H, m, CH); 1.83–1.74 (1H, m) and 1.69–1.59 (1H,
m, CH2); 1.24 (3H, t, J = 7.1, CH3); 1.19 (3H, t, J = 7.1,
CH3); 0.85 (3H, t, J = 7.1, CH3).13C NMR spectrum,
δ, ppm: 167.8; 167.1; 134.2; 129.3; 129.0; 128.4; 90.1;
62.1; 61.6; 54.1; 47.0; 24.5; 14.0; 13.6; 10.5.
from nitrostyrene 9b and malonate 10a. Yield 0.72 g (69%),
1
low-melting solid. The IR, H and 13C NMR spectroscopic
data were in agreement with those of enantiomerically
enriched (1R,2S/1S,2R)-13b and (1R,2R/1S,2S)-13b.
Racemic dimethyl 2-fluoro-2-(2-nitro-1-phenylpropyl)-
malonate (13c) was prepared according to the general
method V from nitrostyrene 9a and malonate 10b. Yield
0.76 g (78%), colorless crystals, mp 70–77°C. The IR,
1H and 13C NMR spectroscopic data were in agreement
with those of enantiomerically enriched (1R,2S/1S,2R)-13c
and (1R,2R/1S,2S)-13c.
1
Compound anti-(1R,2R/1S,2S)-13b. H NMR spectrum,
δ, ppm (J, Hz): 7.23–7.20 (3H, m, H Ph); 7.05–7.01 (2H,
m, H Ph); 4.93–4.87 (1H, m, CH); 4.09–3.75 (6H, m, 2CH,
2CH2); 1.83–1.74 (1H, m) and 1.69–1.59 (1H, m, CH2);
1.13 (3H, t, J = 7.1, CH3); 0.97 (3H, t, J = 7.1, CH3); 0.78
(3H, t, J = 7.2, CH3). 13C NMR spectrum, δ, ppm: 167.2;
166.8; 135.3; 129.3; 129.0; 128.2; 91.6; 62.0; 61.6; 54.6;
48.1; 24.6; 13.8; 13.7; 10.3.
Diethyl (1S,2R)- and (1S,2S)-2-(2-nitro-1-phenylbutyl)-
malonate ((1S,2R)- and (1S,2S)-13b)25a was prepared in
the presence of catalyst Ab according to the general
method I from nitrostyrene 9b and malonate 10a. Yield
0.61 g (72%), low-melting solid. The IR, 1H and 13C NMR
spectroscopic data were in agreement to those established
for the mixture (1R,2S)- and (1R,2R)-13b.
Dimethyl 2-((1R,2S)- and (1R,2R)-2-nitro-1-phenyl-
propyl)malonate ((1R,2S)- and (1R,2R)-13d) and
dimethyl (1S,2R)- and (1S,2S)-2-(2-nitro-1-phenylpropyl)-
malonate ((1S,2R)- and (1S,2S)-13d) were prepared accord-
ing to the general method III or IV from nitrostyrene 9a
and dimethyl malonate (10c). IR spectrum, ν, cm–1:2954,
2916, 2848, 1755, 1557, 1456, 1436. Found, m/z: 318.0946
[M+Na]+. C14H17NNaO6. Calculated, m/z: 318.0948.
1
Compound syn-(1R,2S/1S,2R)-13d. H NMR spectrum,
δ, ppm (J, Hz): 7.26–7.20 (5H, m, H Ph); 5.10 (1H, qd,
J = 6.7, J = 4.5, CH); 4.20 (1H, d, J = 10.9, CH); 3.78 (1H,
dd, J = 10.8, J = 4.5, CH); 3.69 (3H, s, CH3); 3.37 (3H, s,
CH3); 1.37 (3H, d, J = 6.7, CH3). 13C NMR spectrum,
δ, ppm: 168.4; 167.7; 134.0; 128.9; 128.7; 128.6; 83.0;
53.9; 53.1; 52.7; 49.0; 16.93.
Dimethyl (1R,2S)- and (1R,2R)-2-fluoro-2-(2-nitro-
1-phenylpropyl)malonate ((1R,2S)- and (1R,2R)-13c)
was prepared in the presence of catalyst Aa according to
the general method I from nitrostyrene 9a and malonate
10b. Yield 0.49 g (63%), colorless crystals, mp 80–83°C.
IR spectrum, ν, cm–1:2958, 1771, 1757, 1558, 1554, 1361.
13C NMR spectrum: 165.9; 165.6; 165.0; 164.7; 164.6;
164.3; 164.0; 133.4; 132.7; 129.8; 129.7; 129.3; 128.9;
128.8; 128.7; 96.8; 94.7; 85.3; 85.2; 81.8; 54.0; 53.9; 53.3;
53.2; 52.6; 52.4; 18.3; 18.1. 19F NMR spectrum, δ, ppm
(J, Hz): –171.62 (d, J = 29.8); –170.51 (d, J = 29.5).
Found, m/z: 336.0848. [M+Na]+. C14H16FNNaO6. Calcu-
lated, m/z: 336.0854.
1
Compound anti-(1R,2R/1S,2S)-13d. H NMR spectrum,
δ, ppm (J, Hz): 7.14–7.11 (2H, m, Ph); 7.07–6.97 (3H, m,
H Ph); 5.02 (1H, dq, J = 8.0, J = 6.8, CH); 4.09 (1H, dd,
J = 9.3, J = 7.9, CH); 3.84 (1H, d, J = 9.3, CH); 3.65 (3H,
s, CH3); 3.37 (3H, s, CH3); 1.28 (3H, d, J = 6.7, CH3).
13C NMR spectrum, δ, ppm: 168.4; 167.2; 134.7; 129.1;
128.8; 128.6; 84.2; 54.3; 53.0; 52.6; 48.4; 16.4.
Dimethyl (1R,2S)- and (1R,2R)-2-(2-nitro-1-phenyl-
butyl)malonate ((1R,2S)- and (1R,2R)-13e) and dimethyl
(1S,2R)- and (1S,2S)-2-(2-nitro-1-phenylbutyl)malonate
((1S,2R)- and (1S,2S)-13e were prepared according to the
general method III or IV from nitrostyrene 9b and dimethyl
malonate (10c). Low-melting solid. IR spectrum, ν, cm–1:
2955, 1738, 1734, 1550, 1455, 1435, 1262. Found, m/z:
332.1114 [M+Na]+. C15H19NNaO6. Calculated, m/z: 332.1105.
Compound syn-(1R,2S/1S,2R)-13c. 1H NMR spectrum,
δ, ppm (J, Hz): 7.29–7.20 (5H, m, H Ph); 5.09–5.04 (1H,
m, CH); 4.39 (1H, dd, J = 29.5, J = 10.1, CH); 3.89 (3H, s,
CH3); 3.39 (3H, s, CH3); 1.57 (3H, d, J = 6.9, CH3).
1
Compound anti-(1R,2R/1S,2S)-13c. H NMR spectrum,
δ, ppm (J, Hz): 7.29–7.20 (5H, m, H Ph); 5.09–5.04 (1H,
m, CH); 4.43 (1H, dd, J = 29.8, J = 8.0, CH); 3.84 (3H, s,
CH3); 3.44 (3H, s, CH3); 1.26 (3H, d, J = 6.9, CH3).
1
Compound syn-(1R,2S/1S,2R)-13e. H NMR spectrum,
δ, ppm (J, Hz): 7.25–7.20 (3H, m, H Ph); 7.06–7.00 (2H,
m, H Ph); 4.91–4.86 (1H, m, CH); 4.07 (1H, d, J = 10.6,
CH); 3.83–3.78 (1H, m, CH); 3.75 (3H, s, CH3); 3.36 (3H,
s, CH3); 1.82–1.74 (1H, m) and 1.70–1.61 (1H, m, CH2);
0.90 (3H, t, J = 7.3, CH3). 13C NMR spectrum, δ, ppm:
168.3; 167.6; 134.2; 129.1; 128.8; 128.5; 90.1; 53.8; 53.1;
52.7; 47.8; 24.5; 10.5.
Dimethyl (1S,2R)- and (1S,2S)-2-fluoro-2-(2-nitro-
1-phenylpropyl)malonate ((1S,2R)- and (1S,2S)-13c)
was prepared in the presence of catalyst Ab according to
the general method I from nitrostyrene 9a and malonate
10b. Yield 0.40 g (51%), colorless crystals, mp 76–78°C.
1
The IR, H and 13C NMR spectroscopic data were identical
to those established for the mixture (1R,2S/1S,2R)- and
(1R,2R/1S,2S)-13c.
Compound anti-(1R,2R/1S,2S)-13e. 1H NMR spectrum,
δ, ppm (J, Hz): 7.25–7.20 (3H, m, H Ph); 7.06–7.00 (2H,
m, H Ph); 4.96–4.91 (1H, m, CH); 3.96–3.92 (1H, m, CH);
3.79 (1H, d, J = 7.8, CH); 3.60 (3H, s, CH3); 3.33 (3H, s,
CH3); 1.70–1.61 (1H, m) and 1.53–1.42 (1H, m, CH2); 0.78
(3H, t, J = 7.3, CH3). 13C NMR spectrum, δ, ppm: 167.7;
167.3; 135.3; 128.8; 128.5; 128.4; 91.6; 54.4; 52.8; 52.6; 48.1;
25.0; 10.3.
Racemic diethyl 2-(2-nitro-1-phenylpropyl)malonate
(13a) was prepared according to the general method V
from nitrostyrene 9a and malonate 10a. Yield 0.78 g (78%),
1
low-melting solid. The IR, H and 13C NMR spectroscopic
data were in agreement with those of enantiomerically
enriched (1R,2S/1S2R)-13a and (1R,2R, 1S,2S)-13a.
Racemic diethyl 2-(2-nitro-1-phenylbutyl)malonate
(13b) was prepared according to the general method V
Dimethyl (1R,2S)- and (1R,2R)-2-[1-(4-fluorophenyl)-
2-nitropropyl]malonate ((1R,2S)- and (1R,2R)-13f) and
1005

Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
dimethyl (1S,2R)- and (1S,2S)-2-[1-(4-fluorophenyl)-
H Ph); 4.54 (1H, td, J = 10.6, J = 3.1, CH); 3.60–3.55 (1H,
m, CH); 3.43 (3H, s, CH3); 2.69 (1H, dd, J = 15.8, J = 10.5)
and 2.56 (1H, dd, J = 15.7, J = 4.3, CH2); 1.81–1.69 (1H,
m) and 1.45–1.37 (1H, m, CH2); 0.77 (3H, t, J = 7.4, CH3).
13C NMR spectrum, δ, ppm: 170.9; 137.9; 129.1; 128.1;
128.0; 94.1; 51.6; 45.6; 37.7; 25.6; 10.3. Found, m/z:
252.1236 [M+H]+. C13H18NO4.Calculated, m/z: 252.1230.
Methyl (3S,4R)-4-nitro-3-phenylhexanoate ((3S,4R)-17a)
was prepared according to the general method VI from
diastereomeric mixture (1S,2S/1S,2R)-13e. Yield 0.21 g
(46%), low-melting solid. IR spectrum, ν, cm–1: 2954,
2-nitropropyl]malonate ((1S,2R)- and (1S,2S)-13f) were
prepared according to the general method III from
nitrostyrene 9c and dimethyl malonate (10c). Low-melting
solid. IR spectrum, ν, cm–1: 2956, 1737, 1734, 1550, 1512,
1436, 1229, 1165, 846. Found, m/z: 314.1040 [M+H]+.
C14H16FNO6. Calculated, m/z: 314.1034.
1
Compound syn-(1R,2S/1S,2R)-13f. H NMR spectrum,
δ, ppm (J, Hz): 7.04–6.98 (2H, m, H Ph); 6.97–6.88 (2H,
m, H Ph); 5.14–5.05 (1H, m, CH); 4.15 (1H, d, J = 10.8,
CH); 3.73–3.67 (1H, m, CH); 3.75 (3H, s, CH3); 3.39 (3H,
s, CH3); 1.37 (3H, d, J = 6.7, CH3). 13C NMR spectrum,
δ, ppm (J, Hz): 168.2; 167.6; 162.7 (d, J = 248.0); 130.7;
130.6; 115.8; 115.6; 83.0; 53.8; 53.1; 52.8; 48.3; 17.0.
Compound anti-(1R,2R/1S,2S)-13f. 1H NMR spectrum,
δ, ppm (J, Hz): 7.16–7.11 (2H, m, H Ph); 6.97–6.88 (2H,
m, H Ph); 5.04–4.97 (1H, m, CH); 4.12–4.05 (1H, m, CH);
3.79 (1H, d, J = 9.2, CH); 3.65 (3H, s, CH3); 3.46 (3H, s,
CH3); 1.29 (3H, d, J = 6.8, CH3). 13C NMR spectrum,
δ, ppm (J, Hz): 167.5; 167.1; 162.6 (d, J = 248.0); 130.9;
130.4; 115.9; 115.8; 84.0; 54.0; 53.0; 52.7; 47.7; 16.20.
Racemic dimethyl 2-(2-nitro-1-phenylpropyl)malonate
(13d) was prepared according to the general method V.
from β-methyl-β-nitrostyrene (9a) and dimethyl malonate
(10c), low-melting solid. The IR, 1H and 13C NMR spectro-
scopic data were in agreement with those established for
the enantiomerically enriched samples of compound 13d.
Racemic dimethyl 2-(2-nitro-1-phenylbutyl)malonate
(13e) was prepared according to the general method V
from β-ethyl-β-nitrostyrene (9b) and dimethyl malonate
(10c), low-melting solid. The IR, 1H and 13C NMR spectro-
scopic data were in agreement with those established for
the enantiomerically enriched samples of compound 13e.
Racemic dimethyl 2-[1-(4-fluorophenyl)-2-nitropropyl]-
malonate (13f) was prepared according to the general method
V from nitrostyrene 9c and dimethyl malonate (10c),
1
1741, 1608, 1563, 1437, 1360, 1225, 1162, 836. H NMR
spectrum, δ, ppm (J, Hz): 7.26–7.17 (3H, m, H Ph); 7.12–
7.07 (2H, m, H Ph); 4.69–4.64 (1H, ddd, J = 10.5, J = 7.9,
J = 3.7, CH); 3.69–3.58 (1H, m, CH); 3.52 (3H, s, CH3);
2.80 (1H, dd, J = 16.1, J = 6.0) and 2.66 (1H, dd, J = 16.1,
J = 8.7, CH2); 1.95–1.76 (2H, m, CH2); 0.90 (3H, t, J = 7.3,
CH3). 13C NMR spectrum, δ, ppm: 171.4; 137.9; 128.8;
128.0; 127.9; 93.5; 51.9; 45.0; 36.5; 24.5; 10.4. Found, m/z:
252.1237 [M+H]+. C13H18NO4. Calculated, m/z: 252.1230.
Methyl (3S,4S)-4-nitro-3-phenylhexanoate ((3S,4S)-17a)
was prepared according to the general method VI from
diastereomeric mixture (1S,2S/1S,2R)-13e. Yield 0.12 g
(27%), low-melting solid. IR spectrum, ν, cm–1: 2975,
1
1742, 1553, 1436, 1170, 702. H NMR spectrum, δ, ppm
(J, Hz): 7.28–7.19 (3H, m, H Ph); 7.14–7.11 (2H, m, H Ph),
4.54 (1H, td, J = 10.6, J = 3.1, CH); 3.61–3.52 (1H, m,
CH); 3.43 (3H, s, CH3); 2.69 (1H, dd, J = 15.7, J = 10.5)
and 2.56 (1H, dd, J = 15.8, J = 4.3, CH2); 1.81–1.69 (1H,
m) and 1.45–1.37 (1H, m, CH2); 0.77 (3H, t, J = 7.3, CH3).
13C NMR spectrum, δ, ppm: 170.9; 137.9; 129.1; 128.1;
127.7; 94.1; 51.8; 45.6; 37.7; 25.6; 10.3. Found, m/z:
252.1236 [M+H]+. C13H18NO4. Calculated, m/z: 252.1230.
Methyl (3R,4S)-3-(4-fluorophenyl)-4-nitropentanoate
((3R,4S)-17b) was prepared according to the general
method VI from diastereomeric mixture (1R,2S/1R,2R)-13f.
Yield 0.11 g (25%), low-melting solid. IR spectrum, ν, cm–1:
1
colorless crystals, mp 70–77°C. The IR, H and 13C NMR
1
spectroscopic data were in agreement with those established
for the enantiomerically enriched samples of compound
13f.
2954, 1741, 1553, 1437, 1225, 836. H NMR spectrum,
δ, ppm (J, Hz): 7.14–7.04 (2H, m, H Ar); 6.96–6.89 (2H,
m, H Ar); 4.80 (1H, quint, J = 6.9, CH); 3.67–3.59 (1H, m,
CH); 3.52 (3H, s, CH3); 2.78 (1H, dd, J = 16.1, J = 5.9) and
2.65 (1H, dd, J = 16.1, J = 9.0, CH2); 1.48 (3H, d, J = 6.7,
CH3). 13C NMR spectrum, δ, ppm (J, Hz): 171.2; 162.3 (d,
J = 247.1); 133.4 (d, J = 3.4); 129.6 (d, J = 8.2); 115.8 (d,
J = 21.5); 86.4; 52.0; 45.2; 36.2; 16.9. Found, m/z:
256.0847 [M+H]+. C12H14FNO4. Calculated, m/z:
256.0980.
Methyl (3R,4S)-4-nitro-3-phenylhexanoate ((3R,4S)-17a)
was prepared according to the general method VI from
diastereomeric mixture (1R,2S/1R,2R)-13e. Yield 0.23 g
(51%), low-melting solid. IR spectrum, ν, cm–1: 2976,
1737, 1550, 1436, 701. 1H NMR spectrum, δ, ppm (J, Hz);
7.26–7.17 (3H, m, H Ph); 7.12–7.07 (2H, m, H Ph); 4.67
(1H, ddd, J = 10.5, J = 7.9, J = 3.7, CH); 3.67–3.59 (1H, m,
CH); 3.52 (3H, s, CH3); 2.80 (1H, dd, J = 16.1, J = 6.0) and
2.66 (1H, dd, J = 16.1, J = 8.7, CH2); 1.96–1.76 (2H, m,
CH2); 0.90 (3H, t, J = 7.3, CH3). 13C NMR spectrum,
δ, ppm: 171.4; 137.9; 128.8; 128.0; 127.9; 93.5; 51.9; 45.0;
36.5; 24.5; 10.4. Found, m/z: 252.1225 [M+H]+. C13H18NO4.
Calculated, m/z: 252.1230.
Methyl (3S,4R)-3-(4-fluorophenyl)-4-nitropentanoate
((3S,4R)-17b) was prepared according to the general
method VI from diastereomeric mixture (1S,2S/1S,2R)-13f.
Yield 0.16 g (34%), low-melting solid. IR spectrum, ν, cm–1:
2954, 2852, 1738, 1734, 1606, 1550, 1512, 1226, 837.
1H NMR spectrum, δ, ppm (J, Hz): 7.12–7.03 (2H, m,
H Ar); 6.96–6.90 (2H, m, H Ar); 4.80 (1H, dq, J = 7.6,
J = 6.7, CH2); 3.62 (1H, ddd, J = 9.0, J = 7.4, J = 5.7,
CH2); 3.52 (3H, s, CH3); 2.78 (1H, dd, J = 16.1, J = 5.9)
and 2.65 (1H, dd, J = 16.1, J = 9.0, CH); 1.48 (3H, d,
J = 6.7, CH3). 13C NMR spectrum, δ, ppm (J, Hz): 171.2;
162.4 (d, J = 245.0); 133.4; 129.6 (d, J = 8.1); 115.8 (d,
Methyl (3R,4R)-4-nitro-3-phenylhexanoate ((3R,4R)-17a)
was prepared according to the general method VI from
diastereomeric mixture (1R,2S/1R,2R)-13e. Yield 0.11 g
(24%), low-melting solid. IR spectrum, ν, cm–1: 2975,
1
2952, 1742, 1549, 1436, 1260, 702. H NMR spectrum,
δ, ppm (J, Hz): 7.28–7.19 (3H, m, Ph); 7.14–7.11 (2H, m,
1007

Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
J = 21.6); 86.4; 52.0; 45.2; 36.2; 16.9. Found, m/z:
Yield 0.30 g (71%), low melting solid. IR spectrum, ν, cm–1:
3221, 3089, 2965, 2934, 1705, 1454, 701. 1H NMR
spectrum, δ, ppm (J, Hz): 7.28–7.19 (3H, m, H Ph); 7.16–
7.10 (2H, m, H Ph); 6.97–6.80 (1H, m, NH); 3.75–3.66
(2H, m, CH); 2.65–2.56 (2H, m, CH2); 1.06–0.97 (2H, m,
CH2); 0.75 (3H, t, J = 7.4, CH3). 13C NMR spectrum,
δ, ppm: 177.8; 139.2; 128.5; 128.1; 127.1; 60.2; 44.0; 36.0;
24.8; 10.9. Found, m/z: 190.1237 [M+H]+. C12H16NO.
Calculated, m/z: 190.1226.
(4R,5S)-4-(4-Fluorophenyl)-5-methylpyrrolidin-2-one
((4R,5S)-14b) was prepared according to the general
method VII from methyl (3R,4S)-3-(4-fluorophenyl)-
4-nitropentanoate ((3R,4S)-17b). Yield 0.26 g (60%), low-
melting solid. IR spectrum, ν, cm–1: 3246, 2974, 2930,
1699, 1513, 1224, 838. 1H NMR spectrum, δ, ppm (J, Hz):
7.13–7.05 (2H, m, H Ar); 6.97–6.80 (3H, m, H Ar, NH);
4.02–3.94 (1H, m, CH); 3.66 (1H, q, J = 7.8, CH); 2.63–
2.49 (2H, m, CH2); 0.74 (3H, d, J = 6.6, CH3). 13C NMR
spectrum, δ, ppm (J, Hz): 177.6; 161.9 (d, J = 245.6);
134.9; 129.4; 115.4 (d, J = 22.2); 53.7; 43.6; 36.8 (br. s); 17.5.
Found, m/z: 194.0984 [M+H]+. C11H13FNO. Calculated,
m/z: 194.0976.
256.0850 [M+H]+. C12H14FNO4. Calculated, m/z:
256.0980.
Methyl (3S,4S)-3-(4-fluorophenyl)-4-nitropentanoate
((3S,4S)-17b) was prepared according to the general
method VI from diastereomeric mixture (1S,2S/1S,2R)-13f.
Yield 0.09 g (20%), low-melting solid. IR spectrum, ν, cm–1:
3005, 2954, 1741, 1606, 1555, 1511, 1437, 1226, 836.
1H NMR spectrum, δ, ppm (J, Hz): 7.12–7.08 (2H, m,
H Ar); 6.99–6.94 (2H, m, H Ar); 4.69 (1H, dq, J = 9.6,
J = 6.7, CH); 3.62 (1H, td, J = 9.7, J = 4.9, CH); 3.47 (3H,
s, CH3); 2.69 (1H, dd, J = 15.8, J = 10.5) and 2.59 (1H, dd,
J = 15.8, J = 4.3, CH2); 1.27 (3H, d, J = 6.7, CH3). 13C NMR
spectrum, δ, ppm (J, Hz): 172.4; 170.8; 162.3 (d, J = 246.0);
133.3; 129.8 (d, J = 7.8); 116.1 (d, J = 21.6 ); 86.8; 51.9;
45.5; 37.4; 17.6. Found, m/z: 256.0845 [M+H]+. C12H14FNO4.
Calculated, m/z: 256.0980.
(4R,5S)-5-Ethyl-4-phenylpyrrolidin-2-one ((4R,5S)-14a)
was prepared according to the general method VII from
methyl (3R,4S)-4-nitro-3-phenylhexanoate ((3R,4S)-17a).
Yield 0.32 g (77%), low-melting solid. IR spectrum, ν, cm–1:
1
3221, 3087, 2965, 1702, 1454, 701. H NMR spectrum,
δ, ppm (J, Hz): 7.29–7.18 (3H, m, H Ph); 7.15–7.11 (2H,
m, H Ph); 6.72–6.55 (1H, m, NH); 3.75–3.66 (2H, m, CH);
2.63–2.58 (2H, m, CH2); 1.04–0.98 (2H, m, CH2); 0.75
(3H, t, J = 7.4, CH3). 13C NMR spectrum, δ, ppm: 177.7;
139.1; 128.5; 128.1; 127.1; 60.1; 44.1; 35.9; 24.8; 10.8.
Found, m/z: 190.1241 [M+H]+. C12H16NO. Calculated, m/z:
190.1226.
(4R,5R)-4-(4-Fluorophenyl)-5-methylpyrrolidin-2-one
((4R,5R)-14b) was prepared from diastereomeric mixture
(1R,2S)- and (1R,2R)-13f according to the general methods
VI and VII without isolation of intermediate (3R,4S)-17b.
Yield 0.10 g (24%), low-melting solid. IR spectrum, ν, cm–1:
1
3273, 3206, 2973, 2927, 1699, 1694, 1511, 1229. H NMR
spectrum, δ, ppm (J, Hz): 7.22–7.12 (2H, m, H Ar); 7.01–
6.92 (2H, m, H Ar); 6.15 (1H, br. s, NH); 3.68–3.60 (1H,
m, CH); 3.05–2.98 (1H, m, CH); 2.67 (1H, dd, J = 17.0,
J = 8.8) and 2.47 (1H, dd, J = 17.0, J = 10.0, CH2); 1.19
(3H, dd, J = 6.2, CH3). 13C NMR spectrum, δ, ppm: 176.1;
163.2; 160.8; 136.5; 128.9; 127.4; 115.8; 115.6; 57.7; 49.0;
39.3; 20.4. Found, m/z: 194.0990 [M+H]+. C11H12FNO.
Calculated, m/z: 194.0976.
(4R,5R)-5-Ethyl-4-phenylpyrrolidin-2-one ((4R,5R)-14a)
was prepared according to the general method VII from
methyl (3R,4R)-4-nitro-3-phenylhexanoate ((3R,4R)-17a).
Yield 0.31 g (74%), low-melting solid. IR spectrum, ν, cm–1:
3182, 3086, 2906, 2876, 1699, 1668, 1453, 1312, 757.
1H NMR spectrum, δ, ppm (J, Hz): 7.51 (1H, br. s, NH);
7.29–7.23 (2H, m, H Ph); 7.21–7.15 (3H, m, H Ph); 3.49–
3.55 (1H, m, CH); 3.12–3.07 (1H, m, CH); 2.71 (1H, dd,
J = 17.2, J = 9.1) and 2.46 (1H, dd, J = 17.2, J = 8.8, CH2);
1.65–1.53 (1H, m) and 1.53–1.40 (1H, m, CH2); 0.88 (3H,
t, J = 7.4, CH3). 13C NMR spectrum, δ, ppm: 177.3; 142.3;
128.9; 127.3; 127.1; 64.0; 46.9; 39.62; 28.4; 10.5. Found, m/z:
190.1234 [M+H]+. C12H16NO. Calculated, m/z: 190.1226.
(4S,5S)-5-Ethyl-4-phenylpyrrolidin-2-one ((4S,5S)-14a)
was prepared according to the general method VII from
methyl (3S,4S)-4-nitro-3-phenylhexanoate ((3S,4S)-17a).
Yield 0.29 g (70%), low melting solid. IR spectrum, ν, cm–1:
3269, 3169, 3089, 2974, 2923, 1709, 1670, 1514, 818.
1H NMR spectrum, δ, ppm (J, Hz): 7.30–7.24 (2H, m,
H Ph); 7.22–7.17 (3H, m, H Ph); 7.09–6.54 (1H, m, NH);
3.53 (1H, td, J = 7.2, J = 4.7, CH); 3.15–3.04 (1H, m, CH);
2.72 (1H, dd, J = 17.2, J = 9.2, CH2); 2.47 (1H, dd,
J = 17.2, J = 8.8, CH2); 1.64–1.57 (1H, m) and 1.49–1.42
(1H, m, CH2); 0.87 (3H, td, J = 7.4, J = 1.0, CH3).
13C NMR spectrum, δ, ppm: 177.0; 142.2; 128.9; 128.5;
128.1; 127.3; 127.1; 63.8; 46.9; 39.5; 28.3; 10.5. Found, m/z:
190.1231 [M+H]+. C12H16NO. Calculated, m/z: 190.1226.
(4S,5R)-5-Ethyl-4-phenylpyrrolidin-2-one ((4S,5R)-14a)
was prepared according to the general method VII from
methyl (3R,4R)-4-nitro-3-phenylhexanoate ((3S,4R)-17a).
(4S,5S)-4-(4-Fluorophenyl)-5-methylpyrrolidin-2-one
((4S,5S)-14b) was prepared according to the general
method VII from methyl (3S,4S)-3-(4-fluorophenyl)-
4-nitropentanoate ((3S,4S)-17b). Yield 0.28 g (65%), low-
melting solid. IR spectrum, ν, cm–1: 3278, 3198, 3089,
1
2975, 2923, 1709, 1512, 1229, 836. H NMR spectrum,
δ, ppm (J, Hz): 7.30–7.12 (3H, m, H Ar, NH); 6.99–6.92
(2H, m, H Ar); 3.64 (1H, dq, J = 7.5, J = 6.1, CH); 3.00
(1H, ddd, J = 10.0, J = 8.8, J = 7.7, CH); 2.67 (1H, dd,
J = 17.0, J = 8.8) and 2.46 (1H, dd, J = 17.0, J = 10.0,
CH2); 1.18 (3H, d, J = 6.2, CH3). 13C NMR spectrum,
δ, ppm (J, Hz): 176.7; 161.9 (d, J = 245.6); 136.6 (d,
J = 3.0); 128.9 (d, J = 8.1); 115.7 (d, J = 21.2); 115.6; 57.9;
48.9; 39.6; 20.3. Found, m/z: 194.0986 [M+H]+.
C11H12FNO. Calculated, m/z: 194.0976.
(4S,5R)-4-(4-Fluorophenyl)-5-methylpyrrolidin-2-one
((4S,5R)-14b) was prepared according to the general
method VII from methyl (3S,4R)-3-(4-fluorophenyl)-
4-nitropentanoate ((3S,4R)-17b). Yield 0.31 g (71%), low-
melting solid. IR spectrum, ν, cm–1: 3242, 2974, 2931,
1699, 1511, 1224, 838. 1H NMR spectrum, δ, ppm (J, Hz):
7.20–7.15 (2H, m, H Ar); 7.09–7.02 (2H, m, H Ar); 6.34
(1H, br. s, NH); 4.11–4.03 (1H, m, CH); 3.80–3.72 (1H, m,
1007

Chemistry of Heterocyclic Compounds 2020, 56(8), 997–1009
6. Nichols, P. J.; DeMattei, J. A.; Barnett, B. R.; LeFur, N. A.;
CH); 2.75–2.61 (2H, m, CH2); 0.83 (3H, d, J = 6.6, CH3).
13C NMR spectrum, δ, ppm (J, Hz): 177.1; 161.9 (d,
J = 245.7); 134.8; 129.4 (d, J = 8.1); 115.4 (d, J = 21.2);
53.6; 43.5; 35.6; 17.6. Found, m/z: 194.0990 [M+H]+.
C11H12FNO. Calculated, m/z: 194.0976.
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X-ray structural investigation of compounds 13a and G.
Diffraction data of compound 13a were collected at −130°C
on a Bruker-Nonius KappaCCD diffractometer using
monochromated MoKα radiation (λ 0.71073 Å). Crystal of
compound 13a: monoclinic; a 10.9551(5), b 6.8391(2),
c 11.3130(5) Å; β 94.140(2)°; V 845.39(6) Å3; Z 2; μ 0.101 mm–1;
dcalc 1.270 g·cm–3; space group is P21. Diffraction data of
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Rigaku, XtaLAB Synergy, Dualflex, HyPix using
monochromated CuKα radiation (λ 1.54184 Å). Crystal of
catalyst G: monoclinic; a 14.106(2), b 15.400(3), c 21.097(3) Å;
V 4582.8(11) Å3; Z 4; μ 5.338 mm–1; dcalc 1.327 g·cm–3;
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Quantum-chemical calculations were performed
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Tetrahedron 2011, 67, 10186.
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27. Arai, T.; Iimori, Y.; Shirasugi, M.; Shinohara, R.; Takai, Y.;
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29. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, A64, 112.
30. Bochevarov, A. D.; Harder, E.; Hughes, T. F.; Greenwood, J. R.;
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2110.
Supplementary information file containing chiral HPLC
1
data, H and 13C NMR and IR spectra, as well as high-
resolution mass spectra of the synthesized products is available
at the journal website at http://link.springer.com/journal/10593.
This work was supported by the European Regional
Development Fund Project No. 1.1.1.1./16/A/292.
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