Organocatalytic enantioselective synthesis of N-alkyl/aryl-3-alkyl-pyrrolidine-2,5-dione in brine

Article abstract of DOI:10.1016/j.tetasy.2016.09.004

A highly enantioselective approach has been developed for synthesising chiral succinimide derivatives via asymmetric Michael addition of diketones to maleimide using dihydroquinine as a catalyst in brine. The Michael adducts were obtained in yields up to 98% and with enantiomeric excesses up to 98% ee.

Full text of DOI:10.1016/j.tetasy.2016.09.004

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic enantioselective synthesis of N-alkyl/aryl-3-alkyl-
pyrrolidine-2,5-dione in brine
Suhel Mahajan a, Pankaj Chauhan a, Akshay Kumar b, Swapandeep Singh Chimni a,
⇑
a Department of Chemistry, UGC Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar 143005, India
b Department of Chemistry, DAV University, Jalandhar, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective approach has been developed for synthesising chiral succinimide derivatives
via asymmetric Michael addition of diketones to maleimide using dihydroquinine as a catalyst in brine.
The Michael adducts were obtained in yields up to 98% and with enantiomeric excesses up to 98% ee.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 21 July 2016
Accepted 19 September 2016
Available online xxxx
1. Introduction
diketones to maleimide using dihydroquinine as a catalyst in brine
(Fig. 1).
In the past few years, increasing environmental concerns have
encouraged the scientific community to develop sustainable
methodologies for chemical transformations.1 The chemical reac-
tions in the cell are catalysed by enzymes in an aqueous environ-
ment, so taking a cue from this, enzyme mimics can be used to
catalyze chemical reaction in aqueous environments.2 Organocata-
lysts have recently emerged as enzyme mimics3 and have been
used for catalyzing a variety of organic transformations under
aqueous conditions. Amino acids and their derivatives, chiral pri-
mary amines and Cinchona alkaloids have been used as catalysts
under aqueous conditions to deliver products with high enantios-
electivity.4 In recent years asymmetric organocatalytic Michael
additions under aqueous conditions have attracted the attention
of synthetic chemists due to the associated advantages of increased
reaction rates and higher selectivity.5 In all of these literature
2. Results and discussion
Initially, the reaction of acetylacetone 1a with N-benzyl-
maleimide 2b was performed in brine employing 10 mol % of qui-
nine I at 25 °C. The Michael adduct 3ab was obtained in excellent
yield (95%) but with low enantioselectivity (5% ee) (Table 1, entry
1). Other natural Cinchona alkaloids namely cinchonidine II, quini-
dine III and cinchonine IV also provided the Michael adduct 3ab
with similar enantioselectivities (Table 1, entries 2–4). In order
to improve the enantioselectivity of the reaction, we planned to
perform the reaction at the lower temperature of À20 °C. Perform-
ing the reactions at À20 °C, using quinine as the catalyst gave
Michael adduct 3ab with an enantiomeric excess of 71% and a yield
of 98% (Table 1, entry 5). Performing the reaction with other
Cinchona alkaloids, led to the product being obtained with similar
levels of enantiomeric excess (Table 1, entries 6–8). We also stud-
ied the catalytic ability of modified Cinchona alkaloids namely ben-
zylquinine V, benzylcupreine VI and cupreine VII for Michael
addition of 1a to 2b.
The Michael adduct 3ab was isolated in excellent yields
(94–97%) but with lower enantiomeric excesses (Table 1, entries
9–11). When using dihydroquinine as the catalyst, Michael adduct
3ab was obtained with 81% ee. A similar enhancement in terms of
the ee when using dihydroquinine derived squaramide was
observed by Song et al., which was attributed to the increased
hydrophobicity of the catalyst (Table 1, entry 12). A series of
Cinchona thioureas IX–XII were screened for the model reaction,
and the Michael adduct 3ab was obtained in high yield and with
not much change in the enantiomeric excess (Table 1, entries
13–16). Cinchona based squaramide catalysts XIII and XIV
reports, nitroolefins,
a,b-unsaturated aldehydes and a,b-unsatu-
rated ketones have been used as a Michael acceptors, while the
use of maleimide as Michael acceptor under aqueous conditions
remains unexplored. The asymmetric addition of different nucle-
ophiles to maleimides provides easy access to enantiopure succin-
imide derivatives,6 which are the core structural units found in
many natural products and some clinical drug candidates.7 More-
over, chiral succinimides serve as precursors for the synthesis of
biologically important molecules containing pyrrolidine and pyrro-
lidinone (d-lactams) units.8 In continuation of our interests in
developing organocatalytic transformations under aqueous condi-
tions,9 we herein report the asymmetric organocatalytic synthesis
of chiral succinimide derivatives by the Michael addition of
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetasy.2016.09.004
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mahajan, S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.09.004

2
S. Mahajan et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
X
X
X
N
OR
OR
OR
N
N
N
N
H
H
N
H
I
. R = H, X= OMe
V.R = Bn, X = OMe
VI. R = Bn X = OH
III. R = H, X = OMe
IV
II.R = H, X = H
. R = H, X = H
VII
.R = H, X = OH
X
OMe
N
N
N
H
N
H
N
F3C
OH
NH
S
N
H
N
S
NH
CF3
N
X
VIII
F3C
CF3
XI
. X = H
XII. X = OMe
IX
. X = H
X. X = OMe
CF3
F3C
O
OH
Cl
N
HN
O
H
N
N
HN
XV
N
X
XIII
. X = H
XIV. X = OMe
Figure 1. Structure of organocatalysts used.
Table 1
provided Michael adducts 3ab with high yield but with poor enan-
tioselectivity (Table 1, entries 17 and 18).
Catalyst screening for addition of acetylacetone to substituted maleimidesa
The Michael addition of a diketone to N-benzyl maleimide using
dihydroquinine as the catalyst at 0 °C in brine gave product 3ab10
in 91% yield and 40% ee (Table 1, entry 20). Thus, the best opti-
mized condition consists of 10 mol % of dihydroquinine as catalyst,
at À20 °C in brine, which was used to study the substrate scope of
this transformation.
O
O
O
O
O
catalyst 10 mol%
O
N
R1
brine 0.5 mL,
temp°C
R1
*
N
O
1a
2
O
3
2a. R1 = Ph
2b. R1 = Bn
With the optimized conditions in hand, the substrate scope for
the Michael addition of various 1,3-diketones with N-substituted
maleimides was next investigated. The N-benzylmaleimide deriva-
tives bearing electron withdrawing groups on the phenyl ring
reacted efficiently with acetylacetone, to yield Michael adducts
3ac–3af in excellent yields (95–98%) and with good enantioselec-
tivity (52–95% ee). The maleimide derivative with a CF3 group on
the phenyl ring gave Michael adduct 3ag in good yields (92%)
but with poor ee (12%). The Michael addition of acetylacetone to
N-benzylmaleimide bearing an electron releasing group on the
phenyl ring provided products 3ah and 3ai in excellent yield
(97% and 99%) and with high enantioselectivity (98% and 92%),
respectively. The N-methyl maleimide provided the product 3am
with low 9% ee, whereas maleimide resulted in 98% of the product
3an with a lowered enantioselectivity of 24% ee. Next the Michael
addition of 1,3-diphenylpropan-1,3-dione to different derivatives
of maleimides was investigated. The corresponding adducts
3bb–3bk were obtained in excellent yield (92–98%) and with low
to good enantioselectivity (4–93% ee). We also studied the reaction
of 3-substituted 1,3-diketone with N-benzylmaleimide 1b. The
reaction of 1c with 2b provided Michael adducts 3cb with adjacent
quaternary and tertiary carbons in good yield (95%) and 68% ee.
Cyclic 1,3-diketones 1e and 1f provided the Michael adducts with
good enantioselectivity (77% and 86%).
Entry
Catalyst
R
Temperature (°C)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
I
II
III
IV
I
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
25
25
25
95
96
97
94
96
95
97
93
96
96
94
95
97
97
93
94
92
90
—
5 (+)
2 (+)
2 (À)
25
4 (À)
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
0
71 (+)
68 (À)
65 (À)
69 (+)
20 (+)
55 (+)
70 (+)
81 (À)
73 (+)
74 (+)
72 (À)
62 (À)
10 (À)
26 (À)
—
II
III
IV
V
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
I
9
10
11
12
13
14
15
16
17
18
19
20
91
40 (+)
a
Reaction conditions: 0.1 mmol of N-substituted maleimide, 0.11 mmol of
acetylacetone and catalyst in brine 0.5 mL.
b
Isolated yield after column chromatography.
Enantiomeric excess (ee) determined by chiral HPLC.
c
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S. Mahajan et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
O
O
O
O
3ac
yield 98%
ee 52%
3aa
yield 98%
ee 4%
3ab
yield 97%
ee 81%
3ad
yield 97%
ee 95%
F
I
O
O
O
O
O
N
O
O
O
N
O
N
O
O
O
O
Cl
N
Cl
O
CF3
O
Cl
O
Me
3ae
3ah
3af
yield 95%
ee 86%
3ag
yield 92%
ee 12%
CF3
O
yield 95%
ee 68%
yield 94%
ee 98%
O
O
O
O
O
N
O
O
O
O
O
O
N
N
N
O
O
O
O
3al
yield 94%
ee 9%
3ai
yield 98%
ee 92%
3ak
yield 87 %
ee 73%
3aj
OMe
yield 97%
ee 83%
O
O
O
O
O
Ph
Ph
Ph
O
O
O
O
O
Ph
O
O
N
N
N
NH
Ph
Ph
O
O
O
O
3am
yield 96%
ee 24%
3bb
3bd
3bc
yield 98%
ee 90%
yield 94%
ee 68%
yield 98%
ee 40%
F
I
O
O
O
Ph
Ph
O
Ph
O
Ph
O
O
O
O
Ph
O
O
O
N
Cl
N
O
N
Cl
Ph
Ph
N
Ph
CF3
O
Cl
O
O
3bg
yield 93%
ee 15%
3be
yield 96%
ee 43%
3bh
3bf
yield 95%
ee 26%
CF3
yield 93%
ee 75%
Me
O
O
O
Ph
Ph
Ph
O
O
O
O
O
O
Ph
O
O
O
N
N
N
O
N
Ph
Ph
O
O
O
OMe
3bi
yield 94%
ee 50%
3cb
yield 95%
ee 68%
3bj
yield 98%
ee 28%
3bk
yield 97%
ee 4%
O
O
O
O
N
O
O
N
O
O
3eb
yield 70%
ee 86%
3db
yield 67%
ee 77%
In order to demonstrate the practical utility of this protocol, we
performed a gram-scale Michael reaction between 1a and 2b using
10 mol % of catalyst VIII (Scheme 1). The desired Michael adduct
3ab was obtained in 84% yield and without much loss in the
enantioselectivity.
The bifunctional mode of the catalysis by quinidine was demon-
strated by performing a reaction of acetylacetone with N-benzyl
maleimide with catalyst XV, in which the quinuclidine tertiary
amine was converted into a quaternary salt. As expected, the reac-
tion does not occur even after seven days (Table 1, entry 19).
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4
S. Mahajan et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
further purification. Column chromatography was carried out on
a column packed with silica gel 60–120. 1H NMR spectra were
recorded in CDCl3 on a 300 MHz (JEOL AL-300), 400 MHz (JNM-
ECS400) and 500 MHz (BRUKER ADVANCE III) spectrometer. 13C
NMR spectra were recorded in CDCl3 on 75 MHz (JEOL AL-300),
100 MHz (JNM-ECS400), 126 MHz (BRUKER ADVANCE III). Chemi-
cal shifts (d) are expressed in ppm downfield from internal TMS.
Spectroscopic patterns are designated as s = singlet; d = doublet;
dd = doublet of doublet; t = triplet; q = quartet; m = multiplet.
Optical rotation was determined with AUTOPOL IV polarimeter at
25 °C using sodium D light. MS were recorded on micrOTOF-Q II
10356 Mass Spectrometer. HPLC analyses were performed on a
Shimadzu LC-20AD using Daicel Chiralpak IA, IB, IC, AD-H, AS-H
and OD-H columns. Melting points were recorded in glass capillar-
ies using melting point apparatus.
O
O
O
O
O
DHQN(10 mol%)
N
O
Bn
4h, brine
-20°C
N
O
5 mmol
935 mg
2b
Bn
5 mmol
555 mg
1a
84% yield
1.291 g
78% ee
3ab
Scheme 1. Gram scale reaction of acetylacetone with N-benzyl maleimide.
Furthermore, the catalyst BnQN V, bearing no free 9-OH group,
provided the Michael adduct with a lower yield and lower enan-
tioselectivity (Table 1, entry 9). These observations indicate that
the simultaneous activation of both the reactants by the quinu-
clidine moiety and the 9-hydroxyl group of the catalyst is required
for the success of the reaction. In addition to activation, the bifunc-
tional catalyst also provides a favorable orientation for the adduct
formation with high enantioselectivity (Fig. 2).
The Michael adduct can be used to access some biologically
important scaffolds. For example, the diketo group of the adduct
can be converted into benzodiazepines and benzothiazepines,
which are important classes of heterocyclic compounds present
in various drugs and pharmaceuticals.11 Inspired by the biological
importance of benzodiazepines and benzothiazepines, the Michael
adduct 3ab was transformed into 4 (yield 60% ee 65%) and 5 (yield
51% ee 68%), upon the reaction with the 1,2-diaminobenzene and
2-aminothiophenol, respectively (Scheme 2).
4.2. General procedure for the organocatalytic enantioselective
Michael reaction of diketones with maleimide
To a stirred solution of diketone (11.66
dihydroquinine (3.26 mg, 0.1 mol %) in brine (500
l
L, 0.11 mmol) and
L), maleimide
l
(17.30 mg, 0.1 mmol) was added at À20 °C. The progress of the
reaction was monitored by TLC, and upon completion of the reac-
tion (4–5 h), it was extracted three times with ethyl acetate
(3 Â 2 ml). The combined ethyl acetate extract was dried over
anhydrous sodium sulfate and filtered. The filtrate was distilled
to obtain the crude reaction mixture, which was column chro-
matographed using silica gel (60–120 mesh) and eluted with mix-
ture of hexane:ethyl acetate (7: 3) to a obtain pure product.
4.2.1. (S)-3-(2,4-Dioxopentan-3-yl)-1-phenylpyrrolidine-2,5-
3. Conclusion
dione 3aa
Light brown oil; yield: 99%; [
a]
D
20 = À11.6 (c 0.25, CHCl3); enan-
A highly efficient and eco-friendly protocol has been developed
for Michael additions of 1,3-diketones to maleimide in brine by
employing commercially available dihydroquinine as an
organocatalyst. With this methodology, chiral succinimide deriva-
tives were obtained in good yields and with good enantiomeric
excess. The transformations of the Michael adducts to benzodi-
azepine and benzothiazepine derivatives have also been per-
formed. This reaction can be scaled up without much loss in the
ee value of the product. The use of commercially available chiral
molecules as organocatalysts and an experimentally simple proce-
dure are important assets of this methodology.
tiomeric excess: 4% determined by HPLC [Chiralpak AD-H, hexane/
i-PrOH, 80/20, 0.5 mL/min, 210 nm, tR = 47.5 min (minor) and
tR = 51.3 min (major)]; 1H NMR (400 MHz, CDCl3): d 7.46–7.42
(m, 2H), 7.39–7.36 (m, 1H), 7.27–7.25 (m, 2H), 4.21 (d,
J = 5.92 Hz, 1H), 3.30–3.25 (m, 1H), 2.93 (s, 1H), 2.87 (dd,
J1 = 18.28 Hz, J2 = 9.56 Hz, 1H), 2.69 (dd, J1 = 18.28 Hz,
J2 = 5.92 Hz, 1H), 2.34 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 29.9, 30.5, 32.3, 38.9, 65.6, 126.6, 128.8, 129.2, 131.9,
174.9, 177.1, 202.4, 203.1. HRMS (ESI+) m/2 calcd for C16H15FNO4
[(M+H)+]: 274.10 found 274.10.
4.2.2. (S)-1-Benzyl-3-(2,4-dioxopentan-3-yl)pyrrolidine-2,5-
4. Experimental
4.1. General
dione 3ab
Yellow oil; yield: 97%; [
a]
20 = À23.1 (c 0.25, CHCl3); enan-
D
tiomeric excess: 81% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 80/20, 1 mL/min, 210 nm, tR = 37.0 min (major) and
tR = 45.9 min (minor)]; 1H NMR (500 MHz, CDCl3): d 7.38–7.28
(m, 4H), 7.03–6.99 (m, 1H), 4.71–4.60 (m, 2H), 4.26 (d, J = 5.6 Hz,
1H), 3.36–3.30 (m, 1H), 2.81 (dd, J1 = 18.3 Hz, J2 = 9.6 Hz, 1H),
2.59 (dd, J1 = 18.25 Hz, J2 = 5.8 Hz, 1H), 2.36 (s, 3H), 2.19 (s, 3H);
13C NMR (126 MHz, CDCl3): d 30.0, 30.2, 32.2, 39.0, 41.9, 65.6,
115.4, 115.6, 127.9, 128.6, 130.5, 130.6, 175.2, 177.4, 201.8,
202.4. HRMS (ESI+) m/2 calcd for C16H17NO4 [(M+K)+]: 326.08
found 326.08.
All reactions were performed in oven-dried glassware. All sol-
vents and commercially available chemicals were used without
N
Bn
O
N
N
O
O
H
O
4.2.3. (S)-1-(4-Fluorobenzyl)-3-(2,4-dioxopentan-3-yl)pyrro-
H
(S)-isomer
MeO
O
O
lidine-2,5-dione 3ac
O
20 = À13.3 (c 0.25, CHCl3); enan-
O
Yellow oil; yield: 98%; [a]
D
tiomeric excess: 52% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 90/10, 0.5 mL/min, 211 nm, tR = 91.9 min (minor) and
tR = 121.4 min (major)]; 1H NMR (300 MHz, CDCl3): d 7.36–7.32
(m, 2H), 7.01–6.97 (m, 2H), 4.64 (q, J = 11 Hz, 2H), 4.63(d,
J = 5.4 Hz, 1H), 3.34–3.29 (m, 1H), 2.79 (dd, J1 = 18.3 Hz,
Re face
attack
Bn
N
O
Figure 2. Plausible transition state.
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S. Mahajan et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
O
O
NH2
NH2
N
N
S
N
*
NH2
SH
O
*
*
N
reflux, 8h, 10mol% HCl
reflux, 8h, 10mol% HCl
O
O
O
N
O
O
N
4
5
3ab
ee 81%
ield 60%
y
yield 51%
ee 68%
5%
ee 6
Scheme 2. One step transformation of Michael adduct into biologically important benzodiazepine and benzothiazepines heterocyclic compounds.
J2 = 9.3 Hz, 1H), 2.57 (dd, J1 = 18.3 Hz, J2 = 5.7 Hz, 1H), 2.33 (s, 3H),
2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d 30.1, 30.2, 32.3, 39.1,
42.0, 67.8, 115.5, 115.6, 130.6, 130.7, 131.1, 175.4, 177.5, 201.9,
ane/iPrOH, 80/20, 0.5 mL/min, 212 nm, tR = 12.4 min (major) and
tR = 13.4 min (minor)]; 1H NMR (300 MHz, CDCl3): d 7.82–7.83
(m, 3H), 4.28 (q, J = 8.7 Hz, 2H), 4.31 (d, J = 6 Hz, 1H), 3.24–3.31
(m, 1H), 2.70–2.79 (m, 2H), 2.37 (s, 3H), 2.18 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 30.0, 30.6, 32.1, 39.0, 41.8, 65.2, 121.9,
122.1, 122.2, 124.6, 127.8, 128.9, 131.9, 132.2, 137.8, 175.2,
175.7, 201.9, 202.6. HRMS (ESI+) m/2 calcd for C18H15F6NO4 [(M
+H)+]: 424.0984 found 424.0967.
202.5. HRMS (ESI+) m/2 calcd for
C16H17FNO4 [(M+H)+]:
306.1142 found 306.1126.
4.2.4. (S)-1-(4-Iodobenzyl)-3-(2,4-dioxopentan-3-yl)pyrrolidine-
2,5-dione 3ad
Yellow oil; yield: 97%; [
a]
20 = À13.6 (c 0.25, CHCl3); enan-
D
tiomeric excess: 95% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 80/20, 0.5 mL/min, 211 nm, tR = 50.3 min (minor) and
tR = 54.4 min (major)]; 1H NMR (500 MHz, CDCl3): d 7.65 (d,
J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 4.60 (q, J = 27.8 Hz, 2H),
4.26 (d, J = 5.6 Hz, 1H), 3.33–3.29 (m, 1H), 2.79 (dd, J1 = 18.25 Hz,
J2 = 9.4 Hz, 1H), 2.59 (dd, J1 = 18.25 Hz, J2 = 5.85 Hz, 1H), 2.36 (s,
3H), 2.19 (s, 3H); 13C NMR (125 MHz, CDCl3): d 30.0, 30.3, 32.2,
39.0, 42.1, 65.6, 130.6, 130.8, 135.0, 137.7, 137.8, 175.2, 177.4,
201.8, 202.4. HRMS (ESI+) m/2 calcd for C16H16INO4 [(M+H)+]:
41.0202 found 414.0187.
4.2.8. (S)-1-(4-Methylbenzyl)-3-(2,4-dioxopentan-3-yl)pyrro-
lidine-2,5-dione 3ah
Yellow oil; yield: 94%; [
a]
20 = À2.6 (c 0.25, CHCl3); enantiomeric
D
excess: 98% determined by HPLC [Chiralpak AS-H, hexane/iPrOH,
80/20, 0.5 mL/min, 209 nm, tR = 39.5 min (minor) and tR = 47.0 min
(major)]; 1H NMR (500 MHz, CDCl3): d 7.27 (d, J = 7.9 Hz, 2H), 7.13
(d, J = 7.9 Hz, 2H) 4.63 (q, J = 30.45 Hz, 2H), 4.24 (d, J = 6.0 Hz, 1H),
3.35–3.31(m, 2H), 2.80 (dd, J1 = 18.25 Hz, J2 = 9.4 Hz, 1H), 2.55 (dd,
J1 = 18.25 Hz, J2 = 5.8 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H), 2.18 (s, 3H);
13C NMR (126 MHz, CDCl3): d 21.1, 29.9, 32.3, 35.7, 39.0, 42.4, 67.5,
128.6, 128.8, 129.2, 129.4, 132.2, 137.9, 175.3, 177.5, 201.9, 202.5.
HRMS (ESI+) m/2 calcd for C17H19NO4 [(M+H)+]: 3021.1392 found
302.1367.
4.2.5. (S)-1-(2-Chlorobenzyl)-3-(2,4-dioxopentan-3-yl)pyrro-
lidine-2,5-dione 3ae
Yellow oil; yield: 95%; [
a]
20 = À13.5 (c 0.25, CHCl3); 68% enan-
D
tiomeric excess: 95% determined by HPLC [Chiralpak AD-H, hex-
ane/iPrOH, 80/20, 1 mL/min, 254 nm, tR = 18.2 min (major) and
tR = 21.6 min (minor)]; 1H NMR (500 MHz, CDCl3): d 7.38–7.36
(m, 1H), 7.30–7.28 (m, 1H), 7.25–7.22 (m, 2H), 4.82 (s,, 2H), 4.33
(d, J = 5.4 Hz, 1H), 3.38–3.34 (m, 1H), 2.85 (dd, J1 = 18.25 Hz,
J2 = 9.45 Hz, 1H), 2.71 (dd, J1 = 18.25 Hz, J2 = 6.1 Hz, 1H), 2.38 (s,
3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3): d 30.1, 30.4, 32.1,
39.1, 40.4, 65.3, 126.7, 128.8, 128.9, 129.6, 132.4, 132.9 175.2,
177.3, 202.1, 202.6. HRMS (ESI+) m/2 calcd for C16H16ClNO4 [(M
+H)+]: 322.0846 found 322.0831.
4.2.9. (S)-1-(4-Methoxybenzyl)-3-(2,4-dioxopentan-3-yl)pyrro-
lidine-2,5-dione 3ai
Yellow oil, Yield: 98%; [
a
]
D
20 = À13.6 (c 0.25, CHCl3); enan-
tiomeric excess: 92% determined by HPLC [Chiralpak AD-H, hex-
ane/iPrOH, 80/20, 1 mL/min, 254 nm, tR = 22.1 min (major) and
tR = 25.8 min (minor)]; 1H NMR (400 MHz, CDCl3): d 7.35–7.26
(m, 4H), 4.61(t, J = 10 Hz, 1H), 3.78 (s, 3H), 3.35–3.28 (m, 1H),
2.79 (dd, J1 = 24.2 Hz, J2 = 12.4 Hz, 1H), 2.53 (dd, J1 = 24.36 Hz,
J2 = 7.8 Hz, 1H), 2.33 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 30.1, 30.3, 32.3, 35.8, 39.1, 55.4, 65.9, 114.0, 127.8,
130.1, 130.3, 130.5, 134.3, 175.4, 177.6, 202.0, 202.5. HRMS (ESI
+) m/2 calcd for C17H19NO5 [(M+Na)+]: 340.1161 found 340.1156.
4.2.6. (S)-1-(2,3-Dichlorobenzyl)-3-(2,4-dioxopentan-3-yl)pyrro-
lidine-2,5-dione 3af
Yellow oil; yield: 95%; [
a]
20 = À10.3 (c 0.25, CHCl3); enan-
D
tiomeric excess: 86% determined by HPLC [Chiralpak AD-H, hex-
ane/iPrOH, 80/20, 1 mL/min, 254 nm, tR = 14.9 min (minor) and
tR = 19.1 min (major)]; 1H NMR (500 MHz, CDCl3): d 7.46 (d,
J = 1.65 Hz, 1H), 7.39 (d, J = 8.25 Hz, 1H), 7.24–7.21 (m, 1H), 4.60
(q, J = 28.2 Hz, 2H), 4.28 (d, J = 5.35 Hz, 1H), 2.79 (dd, J1 = 14 Hz,
J2 = 5.1 Hz, 1H), 2.60 (dd, J1 = 18.3 Hz, J2 = 5.85 Hz, 1H), 2.35 (s,
3H), 2.19 (s, 3H); 13C NMR (126 MHz, CDCl3): d 30.1, 30.6, 32.2,
39.0, 41.8, 65.2, 126.9, 128.1, 128.9, 130.5, 130.6, 135.5, 175.2,
177.3, 201.9, 202.5. HRMS (ESI+) m/2 calcd for C16H15Cl2NO4 [(M
+Na)+]: 379.1888 found 379.0347.
4.2.10. (S)-1-((Naphthalen-1-yl)methyl)-3-(2,4-dioxopentan-3-
yl)pyrrolidine-2,5-dione 3aj
Yellow solid, mp = 175; yield: 97%; [
a]
20 = À23.5 (c 0.25, CHCl3);
D
enantiomeric excess: 83% determined by HPLC [Chiralpak AD-H,
hexane/i-PrOH, 80/20, 0.5 mL/min, 254 nm, tR = 21.2 min (minor)
and tR = 24.2 min (major)]; 1H NMR (500 MHz, CDCl3): d 8.22 (d,
J = 10.3 Hz, 1H), 7.82 (dd, J1 = 28.25 Hz, J2 = 9.65 Hz, 2H), 7.58–
7.41 (m, 4H), 7.26 (s, 1H), 5.15 (q, J = 46.6 Hz, 2H), 4.25 (d,
J = 6.8 Hz, 1H), 3.30 (d, J = 11.2 Hz, 1H), 2.81(dd, J1 = 22.7 Hz,
J2 = 11.8 Hz, 1H), 2.62 (dd, J1 = 22.8 Hz, J2 = 7.1 Hz, 1H), 2.32 (s,
3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d 30.1, 30.3, 39.1,
65.7, 123.5, 125.4, 125.9, 126.6, 127.6, 128.8, 175.5, 177.7, 202.1,
4.2.7. (S)-1-(3,5-Bis(trifluoromethyl)benzyl)-3-(2,4-dioxopentan-
3-yl)pyrrolidine-2,5-dione 3ag
Yellow oil; yield: 92%; [
a]
20 = À10.8 (c 0.25, CHCl3); enan-
202.6. HRMS (ESI+) m/2 calcd for
C20H19NO4 [(M+Na)+]:
D
tiomeric excess: 12% determined by HPLC [Chiralpak AD-H, hex-
360.1212 found 360.1207.
Please cite this article in press as: Mahajan, S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.09.004

6
S. Mahajan et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.2.11. (S)-3-(2,4-Dioxopentan-3-yl)-1-phenethylpyrrolidine-
4.2.16. (S)-1-(4-Iodobenzyl)-3-(1,3-dioxo-1,3-diphenylpropan-
2,5-dione 3ak
2-yl)pyrrolidine-2,5-dione 3bd
Yellow oil; yield: 96%; [
a
]
20 = À7.2 (c 0.25, MeOH); enan-
Yellowish oil; yield: 94%; [
a
]
D
20 = À19.5 (c 0.25, CHCl3); enan-
D
tiomeric excess: 73% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 85/15, 0.5 mL/min, 254 nm, tR = 68.1 min (major) and
tR = 102.9 min (minor)]; 1H NMR (500 MHz, CDCl3): d 7.33–7.21
(m, 5H), 4.19 (d, J = 6.0 Hz, 1H), 3.81–3.72 (m, 2H), 3.30–3.26 (m,
1H), 2.94–2.88 (m, 2H), 2.78 (dd, J1 = 18.2 Hz, J2 = 9.4 Hz, 1H),
2.52 (dd, J1 = 18.2 Hz, J2 = 5.8 Hz, 1H), 2.35 (s, 3H), 2.21 (s, 3H);
13C NMR (126 MHz, CDCl3): d 30.0, 30.2, 32.1, 33.3, 38.9, 40.2,
65.9, 126.6, 128.5, 128.8, 137.7, 175.4, 177.5, 201.8, 202.1. HRMS
tiomeric excess: 68% determined by [Chiralpak IB, hexane/iPrOH,
90/10, 1 mL/min, 254 nm, tR = 29.2 min (major) and tR = 31.5 min
(minor)]; 1H NMR (400 MHz, CDCl3): d 8.04 (d, J = 7.3 Hz, 2H),
7.78 (d, J = 9.4 Hz, 2H), 7.69–7.52 (m, 6H), 7.38 (t, J = 9.2 Hz, 2H),
7.07 (d, J = 9.7 Hz, 2H), 6.0 (d, J = 4.2 Hz, 1 H), 4.61 (q, J = 39.3 Hz,
2H), 3.40 (t, J = 5.2 Hz, 1H), 3.04 (dd, J1 = 22.9 Hz, J2 = 6.6 Hz, 1H),
2.63 (dd, J1 = 22.9 Hz, J2 = 11.8 Hz, 1H); 13C NMR (126 MHz, CDCl3):
d 31.6, 40.0, 42.1, 54.1, 93.6, 127.2, 128.5, 128.7, 128.9, 129.5,
130.5, 130.6 133.9, 134.3, 134.5, 134.6, 135.2, 137.6, 137.7, 137.8,
175.6, 177.5, 194.6, 195.0. HRMS (ESI+) m/2 calcd for C26H20INO4
[(M+H)+]: 538.0515 found 538.0510.
(ESI+) m/2 calcd for
324.1186.
C17H19NO4 [(M+Na)+]: 324.1212 found
4.2.12. (S)-1-Methyl-3-(2,4-dioxopentan-3-yl)pyrrolidine-2,5-
dione 3al
4.2.17. (S)-1-(2-Chlorobenzyl)-3-(1,3-dioxo-1,3-diphenylpropan-
Yellow oil; yield: 95%; [
a
]
20 = À10.9 (c 0.25, CHCl3); enan-
2-yl)pyrrolidine-2,5-dione 3be
D
tiomeric excess: 9% determined by HPLC [Chiralpak OJ-H, hexane/i-
PrOH, 80/20, 0.5 mL/min, 254 nm, tR = 85.2 min (major) and
tR = 110.9 min (minor)]; 1H NMR (400 MHz, CDCl3): d 4.21 (d,
J = 5.92 Hz, 1H), 3.30–3.25 (m, 1H), 2.93 (s, 3H), 2.74 (dd,
J1 = 18.2 Hz, J2 = 9.36 Hz, 1H), 2.48 (dd, J1 = 18.2 Hz, J2 = 5.72 Hz,
1H), 2.32 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3): d 29.6,
30.2, 33.3, 40.0, 65.5, 176.8, 178.8, 202.4, 203.1. HRMS (ESI+) m/2
calcd for C10H13NO4 [(M+H)+]: 212.0923 found 212.0906.
Yellow oil; yield: 96%; [
a]
D
20 = À19.2 (c 0.25, MeOH); enan-
tiomeric excess: 43% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 90/10, 1 mL/min, 254 nm, tR = 55.2 min (minor) and
tR = 66.1 min (major)]; 1H NMR (400 MHz, CDCl3): d 7.20–8.09
(m, 8H), 6.01 (d, J = 3.0 Hz, 1H), 4.86 (s, 2H), 3.45 (m, 1H), 3.16
(dd, J1 = 18.32 Hz, J2 = 5.8 Hz, 1H), 2.68 (dd, J1 = 18.32 Hz,
J2 = 9.64 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 31.7, 40.2, 40.6,
54.1, 127.1, 127.3, 128.6, 128.7, 128.8, 129.0, 129.6, 132.6, 133.0,
134.1, 134.5, 134.8, 135.4, 175.8, 177.6, 194.8, 195.3. HRMS (ESI
+) m/2 calcd for C26H20ClNO4 [(M+H)+]: 446.1159 found 446.1118.
4.2.13. (S)-3-(2,4-Dioxopentan-3-yl)pyrrolidine-2,5-dione 3am
Yellow oil; yield: 97%; [
a]
20 = À19.2 (c 0.25, CHCl3); enan-
D
tiomeric excess: 24% determined by HPLC [Chiralpak IA, hexane/i-
PrOH, 80/20, 1 mL/min, 284 nm, tR = 17 min (major) and
tR = 46.5 min (minor)]; 1H NMR (300 MHz, CDCl3): d 9.21 (s, 1H,
NH), 4.21 (d, J = 5.4 Hz, 1H), 3.35–3.28(m, 1H), 2.68 (dd,
J1 = 18.3 Hz, J2 = 9.6 Hz, 1H), 2.75–2.66 (dd, J1 = 18.3 Hz,
J2 = 6.3 Hz, 1H), 2.26 (s, 3H), 2.12 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 29.9, 30.2, 33.3, 40.0, 65.5, 176.8, 177.9, 202.4, 203.1. HRMS (ESI
+) m/2 calcd for C9H11NO4 [(M+H)+]: 198.0766 found 198.0734.
4.2.18. (S)-1-(2,3-Dichlorobenzyl)-3-(1,3-dioxo-1,3-diphenyl-
propan-2-yl)pyrrolidine-2,5-dione 3bf
Yellow oil; yield: 95%; [
a]
20 = À23.4 (c 0.25, CHCl3); enan-
D
tiomeric excess: 26% determined by HPLC [Chiralpak AD-H, hex-
ane/iPrOH, 80/20, 0.5 mL/min, 254 nm, tR = 60.7 min (major) and
tR = 65.4 min (minor)]; 1H NMR (500 MHz, CDCl3): d 8.05 (d,
J = 9.6 Hz, 2H), 7.78 (d, J = 9.6 Hz, 2H), 7.69 (t, J = 9.1 Hz, 1H),
7.58–7.52 (m, 3H), 7.49–7.48 (m, 1H), 7.40–7.34 (m, 3H), 7.23–
7.19 (m, 1H), 6.01 (d, J = 4.9 Hz, 1H), 4.68–4.58 (m, 2H), 3.44–
3.39 (m, 1H), 3.08 (dd, J1 = 23.0 Hz, J2 = 6.9 Hz, 1H), 2.65 (dd,
J1 = 22.95 Hz, J2 = 11.9 Hz, 1H).; 13C NMR (100 MHz, CDCl3): d
31.6, 40.8, 41.6, 54.8, 128.1, 128.6, 128.8, 129.0, 129.6, 130.6,
4.2.14. (S)-1-Benzyl-3-(1,3-dioxo-1,3-diphenylpropan-2-yl)
pyrrolidine-2,5-dione 3bb
Yellow oil; yield: 98%; [
a]
20 = À23.6 (c 0.25, CHCl3); enan-
D
tiomeric excess: 90% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 90/10, 1 mL/min, 246 nm, tR = 55.7 min (minor) and
tR = 62.7 min (major)]; 1H NMR(400 MHz, CDCl3): d 7.98–8.06 (m,
2H), 7.80 (d, J = 8.0 Hz, 2H), 7.66–7.69 (m, 1H), 7.49–7.57 (m,
4H), 7.33–7.40 (m, 4H), 7.26–7.29 (m, 2H), 6.01 (d, J = 4.0 Hz,
1H), 4.73–4.77 (m, 1H), 4.62–4.67 (m, 1H), 3.33–3.42 (m, 1H),
3.05 (dd, J1 = 18.2 Hz, J2 = 5.4 Hz, 1H), 2.63 (dd, J1 = 18.4 Hz,
J2 = 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 31.7, 40.2, 42.8,
54.3, 127.3, 127.9, 128.6, 128.7, 128.8, 129.0, 129.6, 132.6, 134.0,
134.6, 134.7, 135.4, 135.7, 175.9, 177.7, 194.7, 195.2. HRMS (ESI
+) m/2 calcd for C26H21NO4 [(M+H)+]: 412.1549 found 412.1543.
134.8, 175.7, 177.6, 194.7, 195.1. HRMS (ESI+) m/2 calcd for C26
-
H19Cl2NO4 [(M+H)+]: 480.0769 found 480.0761.
4.2.19. (S)-1-(3,5-Bis(trifluoromethyl)benzyl)-3-(1,3-dioxo-1,3-
diphenylpropan-2-yl)pyrrolidine-2,5-dione 3bg
Yellow oil; yield: 93%; [
a]
D
20 = À12.8 (c 0.25, MeOH); enan-
tiomeric excess: 15% determined by HPLC [Chiralpak AD-H, hex-
ane/iPrOH, 80/20, 0.5 mL/min, 254 nm, tR = 17.2 min (minor) and
tR = 21.5 min (major)]; 1H NMR (400 MHz, CDCl3): d 8.09 (d,
J = 7.0 Hz, 2H), 7.89 (s, 2H), 7.84–7.86 (m, 4H), 7.69–7.72 (m, 2H),
7.56–7.60(m, 2H), 7.50–7.54 (m, 1H), 7.35–7.39 (m, 2H), 6.03 (d,
J = 4.0 Hz, 1H), 4.74–4.87 (m, 2H), 3.39–3.43 (m, 1H), 3.11 (dd,
J1 = 18.4 Hz, J2 = 5.64 Hz, 1H), 2.62 (dd, J1 = 18.4 Hz, J2 = 9.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 31.6, 40.0, 41.8, 54.2, 121.5,
121.6, 121.9, 124.5, 124.6, 127.8, 128.3, 128.5, 128.7, 129.2,
129.3, 131.4, 131.7, 132.1, 134.1, 134.3, 135.0, 137.9, 175.7,
177.6, 194.7, 195.2. HRMS (ESI+) m/2 calcd for C28H19F6NO4 [(M
+H)+]: 548.1297 found 548.1281.
4.2.15. (S)-1-(4-Fluorobenzyl)-3-(1,3-dioxo-1,3-diphenylpropan-
2-yl)pyrrolidine-2,5-dione 3bc
Yellow oil; yield: 98%; [
a]
20 = À19.0 (c 0.25, CHCl3); enan-
D
tiomeric excess: 40% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 90/10, 1 mL/min, 209 nm, tR = 54.6 min (major) and
tR = 57.3 min (minor)]; 1H NMR (500 MHz, CDCl3): d 8.06 (d,
J = 7.3 Hz, 2H), 7.81 (d, J = 7.3 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H),
7.58–7.53 (m, 3H), 7.41–7.33 (m, 2H), 7.36–7.33 (m, 1H), 7.03–
6.95 (m, 1H), 6.03 (d, J = 4.2 Hz, 1H), 4.67 (q, J = 42.1 Hz, 2H),
3.44–3.39 (m, 1H), 3.05 (dd, J1 = 18.4 Hz, J2 = 5.6 Hz, 1H), 2.64
(dd, J1 = 18.2 Hz, J2 = 9.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
31.6, 40.1, 42.0, 54.2, 115.4, 115.6, 115.8, 128.6, 128.8, 129.0,
129.6, 130.6, 175.9, 177.6, 194.7, 195.2. HRMS (ESI+) m/2 calcd
for C26H20FNO4 [(M+H)+]: 430.1455 found 430.1448.
4.2.20. (S)-1-(4-Methylbenzyl)-3-(1,3-dioxo-1,3-diphenyl-
propan-2-yl)pyrrolidine-2,5-dione 3bh
Yellow oil; yield: 93%; [
a
]
20 = À3.8 (c 0.25, MeOH); enan-
D
tiomeric excess: 75% determined by HPLC [Chiralpak OD-H, hex-
ane/iPrOH, 80/20, 1 mL/min, 254 nm, tR = 17.6 min (maJor) and
tR = 22.8 min (minor)]; 1H NMR (500 MHz, CDCl3): d 8.09 (d,
J = 7.7 Hz, 2H), 7.82 (d, J = 7.8 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.58
Please cite this article in press as: Mahajan, S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.09.004

S. Mahajan et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
– 7.52 (m, 3H), 7.40 (t, J = 7.8 Hz, 2H), 7.27(t, J = 41.3 Hz, 2H), 7.10
(d, J = 7.8 Hz, 2H), 6.03 (d, J = 4.2 Hz, 1H), 4.73 (d, J = 14.2 Hz, 1H),
4.62 (d, J = 14.3 Hz, 1H), 3.48–3.33 (m, 1H), 3.05 (dd, J1 = 18.3 Hz,
J2 = 5.65 Hz, 1H), 2.64 (dd, J1 = 18.25 Hz, J2 = 9.6 Hz, 1H), 2.33 (s,
3H); 13C NMR (126 MHz, CDCl3): d 21.1, 29.7, 31.5, 40.0, 42.4,
54.2, 128.4, 128.5, 128.7, 128.8, 129.2, 129.4, 132.7, 133.8,
134.5,135.3, 137.4, 175.5, 177.7, 194.6, 195.0. HRMS (ESI+) m/2
calcd for C27H19NO4 [(M+Na)+]: 448.1525 found 448.1587.
128.2, 128.7, 128.8, 135.6, 175.2, 177.2, 204.9, 205.3. HRMS (ESI
+) m/2 calcd for C17H19NO4 [(M+H)+]: 302.1392 found 302.1359.
4.2.25. (S)-1-Benzyl-3-(1-methyl-2,6-dioxocyclohexyl)pyrro-
lidine-2,5-dione 3db
Brown oil; yield: 67%; [
a]
20 = À8.4 (c 0.25, CHCl3); enantiomeric
D
excess: 77% determined by HPLC [Chiralpak IA, hexane/iPrOH,
90/10, 1 mL/min, 254 nm, tR = 26.2 min (minor) and tR = 45.5 min
(major)]; 1H NMR(300 MHz, CDCl3): d 7.16–7.26 (m, 5H), 4.54 (q,
J = 35.4 Hz, 2H), 3.54 (t, J = 9.0 Hz, 1H), 2.43–2.74 (m, 6H), 2.02–
2.03 (m, 1H), 1.81 (m, 1H), 1.43 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 17.1, 22.2, 32.6, 37.2, 42.2, 42.3, 43.1, 65.1, 127.6, 128.3, 128.5,
135.5, 135.6, 175.7, 178.4, 208.0, 209.5. HRMS (ESI+) m/2 calcd
for C18H19NO4 [(M+Na)+]: 336.1212 found 336.1220.
4.2.21. (S)-1-(4-Methoxybenzyl)-3-(1,3-dioxo-1,3-diphenyl-
propan-2-yl)pyrrolidine-2,5-dione 3bi
Yellow oil; yield: 94%; [
a]
20 = À18.8 (c 0.25, MeOH); enan-
D
tiomeric excess: 50% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 90/10, 1 mL/min, 254 nm, tR = 86.8 min (major) and
tR = 102.8 min (minor)]; 1H NMR (500 MHz, CDCl3): d 8.11–8.06
(d, J = 7.4 Hz, 2H), 7.82 (d, J = 7.4 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H),
7.58–7.50 (m, 3H), 7.41–7.28 (m, 5H), 6.86–6.80 (m, 2H), 6.02 (d,
J = 4.2 Hz, 1H), 4.71–4.58 (m, 2H), 3.79 (s, 3H), 3.41–3.39 (m, 1H),
3.04 (dd, J1 = 18.25 Hz, J2 = 5.6 Hz, 1H), 2.68–2.60 (dd,
J1 = 18.3 Hz, J2 = 9.45 Hz, 1H); 13C NMR (126 MHz, CDCl3): d 31.5,
40.0, 42.1, 55.2, 67.4, 113.8, 114.0, 127.1, 127.3, 127.9, 128.4,
128.7, 128.8, 129.4, 130.0, 130.4, 132.4, 133.8, 134.1, 134.5,
135.6, 175.7, 177.5, 194.5, 195.0. HRMS (ESI+) m/2 calcd for
4.2.26. (S)-1-Benzyl-3-(1-methyl-2,5-dioxocyclopentyl)pyrro-
lidine-2,5-dione 3eb
Brown oil; mp, 144–145 °C; yield: 70%; [
a]
20 = À7.6 (c 0.25,
D
CHCl3); enantiomeric excess: 86% determined by HPLC [Chiralpak
IA, hexane/iPrOH, 90/10, 1 mL/min, 254 nm, tR = 19.6 min (major)
and tR = 36.5 min (minor)]; 1H NMR(400 MHz, CDCl3): d 7.26–
7.22 (m, 5H), 4.54 (q, J = 31.48 Hz, 2H), 3.37 (dd, J1 = 9.36 Hz,
J2 = 7.12 Hz, 1H), 3.10 (dd, J1 = 17.56 Hz, J2 = 7.04 Hz, 1H), 2.83–
2.85 (m, 2H), 2.81–2.82 (m, 2H), 2.76–2.78 (m, 1H), 1.19 (s, 3H);
13C NMR (100 MHz, CDCl3): d 19.0, 30.8, 34.8, 35.0, 42.4, 45.4,
53.5, 127.9, 128.3, 128.6, 135.3, 175.0, 177.6, 213.3, 216.6. HRMS
C27H23NO5 [(M+H)+]: 442.1654 found 442.1648.
4.2.22. (S)-1-((Naphthalen-1-yl)methyl)-3-(1,3-dioxo-1,3-diphenyl-
propan-2-yl)pyrrolidine-2,5-dione 3bj
(ESI+) m/2 calcd for
C17H17NO4 [(M+H)+]: 300.1236 found
Brown solid, mp = 187; yield: 98%; [
a]
D
20 = À22.9 (c 0.25, CHCl3);
300.1223.
enantiomeric excess: 28% determined by HPLC [Chiralpak AS-H,
hexane/iPrOH, 90/10, 1.0 mL/min, 254 nm, tR = 78.7 min (minor)
and tR = 92.8 min (major)]; 1H NMR (500 MHz, CDCl3): d 8.22 (d,
J = 10.4 Hz, 1H), 8.02 (d, J = 9.4 Hz, 2H), 7.85–7.86 (m, 4H), 7.66
(t, J = 9.3 Hz, 1H), 7.57–7.48 (m, 6H), 7.41–7.34 (m, 3H), 6.03 (d,
J = 4.1 Hz, 1H), 5.25 (d, J = 18.6 Hz, 1H), 5.12 (d, J = 18.7 Hz, 1H),
3.42–3.47 (m, 1H), 3.10 (dd, J1 = 22.8 Hz, J2 = 7.05 Hz, 1H), 2.64
(dd, J1 = 22.9 Hz, J2 = 12 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
31.6, 40.0, 40.7, 54.2, 125.4, 127.4, 128.5, 128.6, 128.8, 128.9,
129.6, 176.0, 177.9, 194.9, 195.3. HRMS (ESI+) m/2 calcd for
4.2.27. 1-Benzyl-3-(2,4-dimethyl-3H-benzo[b][1,4]diazepin-3-
yl)-3k3-pyrrolidine 2,5-dione 4
Brown viscous oil; yield: 60%; enantiomeric excess: 65% deter-
mined by HPLC [AS-H, hexane/iPrOH, 80/20, 1 mL/min, 210 nm,
tR = 37.0 min (major) and tR = 45.9 min (minor)]; 1H NMR
(500 MHz, CDCl3): d 8.23 (d, J = 10 Hz, 1H), 7.86–7.87 (m, 3H),
7.66–7.35 (m, 4H), 7.26 (s, 1H), 5.15 (dd, J1 = 45 Hz, J2 = 15 Hz,
2H), 4.25 (d, J = 5 Hz, 1H), 3.30 (d, J = 15 Hz, 1H), 2.81 (dd,
J1 = 25 Hz, J2 = 15 Hz, 1H), 2.62 (dd, J1 = 20 Hz, J2 = 5 Hz), 2.32 (s,
6H); 13C NMR (126 MHz, CDCl3): d 29.8, 34.6, 35.6, 36.9, 42.5,
43.4, 117.5, 122.9, 125.4, 125.96, 127.6, 127.9, 128.6, 128.7,
128.8, 132.5, 135.7, 138.1, 15.9, 179.0 HRMS (ESI+) m/2 calcd for
C30H23NO4 [(M+H)+]: 462.1705 found 462.1706.
4.2.23. (S)-3-(1,3-Dioxo-1,3-diphenylpropan-2-yl)-1-phenethyl-
pyrolidine-2,5-dione 3bk
Yellow oil; yield: 97%; [
a]
20 = À15.0 (c 0.25, CHCl3); enan-
C22H21N3O2 [(M+H)+]: 360.1712 found 360.1702.
D
tiomeric excess: 4% determined by HPLC [Chiralpak AS-H, hex-
ane/iPrOH, 80/20, 1 mL/min, 254 nm, tR = 51.6 min (major) and
tR = 62.3 min (minor)]; 1H NMR (500 MHz, CDCl3): d 8.10–8.02
(m, 2H), 7.85 (d, J = 7.5 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 7.60–7.50
(m, 3H), 7.42 (t, J = 7.8 Hz, 2H), 7.32–7.22 (m, 5H), 6.04 (d,
J = 4.2 Hz, 1H), 3.81–3.75 (m, 2H), 3.41–3.37 (m, 1H), 3.02 (dd,
J1 = 18.2 Hz, J2 = 5.5 Hz, 1H), 2.96–2.81 (m, 2H), 2.62 (dd,
J1 = 18.25 Hz, J2 = 9.6 Hz, 1H); 13C NMR (126 MHz, CDCl3): d 31.6,
33.5, 35.8, 40.3, 54.5, 126.6, 127.2, 128.1, 128.5, 128.6, 128.7,
128.8, 128.9, 129.0, 129.5, 132.5, 133.9, 134.6, 135.4, 135.6,
138.1, 175.9, 177.7, 194.8, 196.1. HRMS (ESI+) m/2 calcd for
4.2.28. 1-Benzyl-3-(2,4-dimethylbenzo[b][1,4]thiazepin-3-yl)-
3k3-pyrrolidine-2,5-dione 5
Brown viscous oil; yield: 51%; enantiomeric excess: 68% deter-
mined by HPLC [Chiralpak AD-H, hexane/iPrOH, 80/20, 0.5 mL/min,
233 nm, tR = 17.2 min (minor) and tR = 21.3 min (major)]; 1H NMR
(500 MHz, CDCl3): d 7.40 (d, J = 10 Hz, 2H), 7.35–7.28 (m, 5H),
7.27–7.20 (m, 3H), 4.73–4.63 (m, 2H), 2.97–2.88 (m, 2H), 2.56 (t,
J = 15 Hz, 1H), 2.19 (s, 3H), 1.79 (s, 3H); 13C NMR (126 MHz, CDCl3):
d 29.8, 34.6, 35.6, 42.5, 43.4, 117.5, 122.8, 125.4, 125.9, 127.4,
127.6, 127.8, 128.6, 128.7, 128.8, 128.9, 132.5, 133.5, 135.7,
138.1, 175.9, 179.0. HRMS (ESI+) m/2 calcd for C22H20N2O2S [(M
+H)+]: 377.1324 found 377.1338.
C27H23NO4 [(M+H)+]: 426.1705 found 426.1678.
4.2.24. (S)-1-Benzyl-3-(3-methyl-2,4-dioxopentan-3-yl)pyrro-
lidine-2,5-dione 3cb
Acknowledgements
Yellow oil; yield: 95%; [
a]
20 = À81.5 (c 0.25, CHCl3); enan-
D
tiomeric excess: 68% determined by HPLC [Chiralpak IA, hexane/i-
PrOH, 90/10, 1 mL/min, 254 nm, tR = 19.8 min (minor) and
tR = 21.5 min (major)]; 1H NMR (400 MHz, CDCl3): d 7.34–7.24
(m, 5H), 4.60 (q, J = 27.96 Hz, 2H), 3.56 (dd, J1 = 9.36 Hz,
J2 = 5.56 Hz, 1H), 2.83–2.93 (m, 1H), 2.32–2.34 (dd, J1 = 18.44 Hz,
J2 = 5.52 Hz, 1H), 2.24 (s, 3H), 2.12 (s, 3H), 1.42 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 16.2, 26.4, 27.0, 32.3, 42.6, 42.7, 44.2, 128.0,
This work was supported by the CSIR research scheme [02
(0239)/15/EMR-II] sanctioned to SSC. Financial support from the
Department of Science and Technology (DST), India under FIST pro-
gramme and UGC, India, under CAS-I and UPE programme are
gratefully acknowledged. We thank Prof. Palwinder Singh for help
in running HRMS and NMR experiments.
Please cite this article in press as: Mahajan, S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.09.004

8
S. Mahajan et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Supplementary data
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