Calixarene-based chiral primary amine thiourea promoted highly enantioselective asymmetric Michael reactions of α,α-disubstituted aldehydes with maleimides

Article abstract of DOI:10.1016/j.tetasy.2013.09.010

Calix[4]arene based chiral bifunctional thiourea-primary amines have been shown to act as effective catalysts for the Michael addition of aldehydes to maleimides for the first time. The corresponding adducts were generally obtained preferentially in (R)-

Full text of DOI:10.1016/j.tetasy.2013.09.010

Tetrahedron: Asymmetry 24 (2013) 1443–1448
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Calixarene-based chiral primary amine thiourea promoted highly
enantioselective asymmetric Michael reactions of
aldehydes with maleimides
a,a-disubstituted
⇑
Mustafa Durmaz, Abdulkadir Sirit
Department of Chemistry, Necmettin Erbakan University, 42099 Meram, Konya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2013
Accepted 13 September 2013
Available online 29 October 2013
Calix[4]arene based chiral bifunctional thiourea-primary amines have been shown to act as effective cat-
alysts for the Michael addition of aldehydes to maleimides for the first time. The corresponding adducts
were generally obtained preferentially in (R)- or (S)-forms with high yields (up to 99%) and with high to
excellent enantioselectivities (up to 98% ee).
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
to maleimides that were catalyzed by primary amine-thiourea
catalysts derived from 1,2-cyclohexanediamine as the chiral
Organocatalysis has emerged as an extremely useful method for
the synthesis of potentially important optically active compounds.
In addition to chiral metal complexes, enzymes, and other biocata-
lysts, organocatalysts have been employed as chiral tools to pro-
mote a variety of asymmetric reactions for many years.1
Organocatalysts offer a number of advantages in terms of
widespread applicability, operational simplicity, environmental
compatibility, reusability, high efficiency, and selectivity.2 There-
fore, the design and synthesis of new effective catalysts is a rapidly
growing and competitive research area in synthetic organic
chemistry.
The catalytic asymmetric Michael addition is one of the most
important approaches to carbon–carbon bond formation in asym-
metric synthesis. To date, many asymmetric Michael additions of
nucleophiles to a variety of Michael acceptors promoted by chiral
organocatalysts have been reported.3 However, the use of malei-
mides as Michael acceptors is relatively rare. The Michael addition
of carbonyl compounds to maleimides is of particular interest to
source. Recently, Miura et al. have described the asymmetric
Michael reactions of maleimides with aldehydes by a recyclable
fluorous organocatalyst.6
Calixarenes, cyclic oligomers of phenolic units linked through
the ortho-positions, are an interesting class of macrocycles.7 The
introduction of chiral substituents into the calixarene macrocyclic
ring either by attaching chiral units at one of the calix rims, or by
synthesizing ‘inherently’ chiral derivatives could, in turn, lead to
chirality of the artificial receptors.8 Thus, chiral calixarene deriva-
tives obtained in this way might be good candidates as chiral
catalysts for the organocatalytic preparation of chiral compounds.
Despite the increasing use of chiral calixarenes for the separation,9
recognition,10 and discrimination11 of biologically active com-
pounds, only a few calixarene derivatives have been reported as
organocatalysts12,13 for asymmetric transformations.
To the best of our knowledge, no examples have been reported
so far on the organocatalytic Michael reaction of isobutyraldehyde
with maleimides catalyzed by calix[4]arenes.
provide a-substituted succinimides, which play an important role
as precursors of biologically active compounds or chiral building
blocks in synthetic and medicinal chemistry.
2. Results and discussion
In 2007, the asymmetric Michael reaction of maleimides with
aldehydes was first described by Cordova et al. using diphenylpro-
linol silyl ether as a catalyst and moderate chemical yield and
enantioselectivity were observed with sterically hindered
Over the course of our studies on the synthesis of chiral
receptors equipped with various functionalities to aid their
catalytic activities14 and enantiomeric recognition properties,15
we recently synthesized two calix[4]arene-based chiral receptors16
and used them as catalysts in Michael reactions of aldehydes with
b-nitroolefins (Scheme 1). Herein we report the enantioselective
Michael addition of isobutyraldehyde to maleimides promoted by
chiral calix[4]arene derivatives bearing two primary amine-
thiourea units in excellent yields (up to 99%) and enantioselectiv-
ities (up to 98% ee).
a,a
-disubstituted aldehydes such as isobutyraldehyde.4 Since
then,
a
number of research groups5 have reported highly
enantioselective Michael additions of
a,a-disubstitued aldehydes
⇑
Corresponding author. Tel.: +90 332 3238220/5822; fax: +90 332 3238225.
E-mail address: asirit42@yahoo.com (A. Sirit).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.09.010

1444
M. Durmaz, A. Sirit / Tetrahedron: Asymmetry 24 (2013) 1443–1448
O
O
N
N
NH2
H2N
1
2
1'
2'
1
2
1'
2'
O
O
HN
HN
NH
NH
NH
NH
HN
HN
S
S
S
S
NH2
O
H2N
O
O
O
HO OH
HO OH
O
HO OH
O
ii
i
2a: (1R,2R,1'R,2'R) 91%
2b: (1S,2S,1'S,2'S) 88%
1a
3a: (1R,2R,1'R,2'R) 84%
3b: (1S,2S,1'S,2'S) 82%
O
N
H2N
HN
H2N
O
HN
O
HN
S
HN
O
S
i
ii
89%
90%
O
1b
3c
2c
Scheme 1. Synthesis of calix[4]arene-based primary amine thiourea organocatalysts 3a, 3b (top), and p-tert-butylphenol analogue 3c (bottom). Reagents and conditions: (i)
chiral isothiocyanate, CH2Cl2, rt, 24 h; (ii) N2H4ꢀH2O, EtOH, reflux.
We initially focused on solvent effects in the Michael reactions
at ambient temperature; the Michael addition of isobutyraldehyde
4 to N-phenylmaleimide 5 was selected as a model reaction in the
presence of organocatalysts (15 mol %) 3a–3c. As summarized in
Table 1, the Michael addition proceeded smoothly in CH2Cl2 to
afford the desired products in up to 99% yields and with excellent
stereoselectivities (83–95% ee) (Table 1, entries 1–3) at room tem-
perature, whereas using nonpolar solvents, such as CCl4 and tolu-
ene resulted in similar yields and enantioselectivities (Table 1,
entries 4 and 5). Furthermore, the use of CHCl3, Et2O, EtOAc, THF,
and 1,2-DCE slightly decreased the reactivity and enantioselectivi-
ty (Table 1, entries 6–10), whereas using protic solvents such as
iPrOH or MeOH afforded the Michael product in lower yields and
enantioselectivity (Table 1, entries 14 and 15).
Having identified the best solvent and reaction medium, we
next examined the effect of catalyst loading on the reaction.
Catalyst loadings, ranging from 10 to 2 mol %, were evaluated.
Excellent chemical yields without a compromise to the enantiose-
lectivity of the reaction were obtained when using catalyst
loadings of 10 mol % (Table 2, entry 1). However, decreasing the
catalyst loading to 5 and 2 mol % reduced the reaction rate along
with a loss of the enantiomeric excess (Table 2, entries 2 and 3).
The addition of a catalytic amount of Brønsted acid may
promote the formation of the enamine species and subsequently
improve reactivity. In order to test this, various organic acids were
used as additives (10 mol %) in the reaction mixture. A slight
decrease in enantioselectivities and chemical yields were observed
when the reaction was carried out in the presence of benzoic acid,
acetic acid, phenyl glycine, or (S)-1,10-bi-2-naphthol (Table 2,
entries 4, 7, 9, and 10). Adduct 6a0 was obtained in trace amounts
when 10 mol % of TFA or DMAP was used (Table 2, entries 8 and
11).
With the optimal reaction conditions in hand, we next probed
the scope of the chiral calix[4]arene 3a and 3b-catalyzed reaction
with a set of aldehydes and maleimides (Table 3). All reactions
were performed in CH2Cl2 in the presence of 10 mol % of catalyst
3a or 3b. Various aromatic substituted maleimides reacted well
with aldehyde donors to give the desired Michael products
6b/6b0–6r/6r0 in 55–99% yields and with different enantioselectiv-
ities (Table 3, entries 1–17). The results in Table 3 also indicate that

M. Durmaz, A. Sirit / Tetrahedron: Asymmetry 24 (2013) 1443–1448
1445
Table 1
calixarene platform of 3a and 3b in this reaction. The enantioselec-
tive Michael addition of isobutyraldehyde 4 to N-phenylmaleimide
5 in CH2Cl2, for 2.5 h afforded the (S)-Michael product in a lower
yield and enantioselectivity (Table 1, entry 3) than the calixa-
rene-based chiral primary amine–thiourea derivatives. As reported
earlier,17 these results showed that the presence of the bulky calix-
arene moiety of the thiourea and the phenolic hydroxy groups on
the calixarene scaffold as acidic additives play a crucial role in
helping increase the electrophilicity of maleimide and preorganis-
ing the reaction substrates.
Optimization of the asymmetric Michael addition of isobutyraldehyde
4 to
N-phenylmaleimide 5 catalyzed by 3a–3ca
O
O
O
O
catalyst (15 mol%)
solvent, rt
N
Ph
*
+
N
Ph
H
H
O
O
6a/6a'
4
5
Although the precise reaction mechanism to explain the high
enantioselectivity observed in Michael additions catalyzed by
calix[4]arene-based chiral primary amine–thiourea derivatives
needs further study, we propose that the reaction proceeds via a
dual activation model. The aldehyde is activated by the primary
amine group of 3a or 3b through the enamine intermediate, while
the thiourea moiety of the catalyst directs and activates the malei-
mide by hydrogen-bonding interactions simultaneously. The
attack of this enamine from the re- or si-face of the maleimide
leads to the formation of addition products 6 with an (R)- or
(S)-configuration.
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
CH2Cl2
CH2Cl2
CH2Cl2
CCl4
Toluene
CHCl3
Et2O
EtOAc
THF
1,2-DCE
Acetonitrile
1,4-Dioxane
MTBE
i-PrOH
MeOH
0.5
0.5
2.5
0.5
0.5
0.5
0.5
1.5
3
99
99
76
99
99
98
94
96
85
98
74
82
87
45
30
92 (R)
95 (S)
83 (S)
91 (S)
90 (S)
85 (S)
84 (S)
78 (S)
81 (S)
86 (S)
71 (S)
73 (S)
70 (S)
45 (S)
17 (S)
9
10
11
12
13
14
15
0.5
2
3
2
6
6
3. Conclusion
In conclusion, new calix[4]arene-based chiral bifunctional pri-
mary amine–thiourea catalysts 3a and 3b have been developed
as efficient organocatalysts for the asymmetric Michael addition
of aldehydes to maleimides. The reactions proceeded smoothly in
CH2Cl2 at ambient temperature to give high yields (up to 99%)
and ee (up to 98%) with broad substrate scope. Chiral catalyst 3a
preferentially furnished the (R)-enantiomer, whereas 3b selec-
tively produced the (S)-enantiomer. Further studies of this catalytic
system in other asymmetric C–C bond forming processes are cur-
rently underway.
a
All reactions were carried out with isobutyraldehyde 4 (0.40 mmol), N-phen-
ylmaleimide 5 (0.20 mmol), and the catalyst (0.03 mmol) in solvents (0.5 mL).
b
Isolated yields after column chromatography on SiO2.
Determined by chiral HPLC analysis (Chiralcel OD-H).
The absolute configuration was determined by comparison with the literature
c
d
data.
Table 2
Screening of catalyst loading and additives for 3b-catalyzed addition of isobutyral-
dehyde 4 to N-phenylmaleimide 5a
O
O
4. Experimental
4.1. General
O
O
3b (10 mol%)
additive (10 mol%)
(S)
N
Ph
+
N
Ph
H
H
CH2Cl2, rt
O
O
5
Melting points were determined on an Electrothermal 9100
apparatus in a sealed capillary. 1H and 13C NMR spectra were
recorded in CDCl3 at room temperature on Varian 400 and Bruker
400 instruments. Chemical shifts are reported in ppm. Data are
reported as follows: chemical shift (ppm), multiplicity (s = singlet,
d = doublet, t = triplet, m = multiplet, br = broad), and coupling con-
stants (Hz). Infrared (IR) spectra were recorded on a Perkin Elmer
spectrum-100 FTIR spectrometer equipped with an ATR unit and
are reported in wavenumbers (cm–1). The HPLC measurements
were carried out on Agilent 1100 equipment connected with
Chiralpak Daicel AD-H, OD-H, and AS-H columns. Optical rotations
were measured on an Atago AP-100 digital polarimeter using a
1 dm cell. Elemental analyses were performed using a Leco CHNS-
932 analyzer. Analytical TLC was performed using Merck prepared
plates (silica gel 60 F254 on aluminum). Flash chromatography sep-
arations were performed on a Merck Silica Gel 60 (230–400 Mesh).
All starting materials and reagents used were of standard analytical
grade from Fluka, Merck, Aldrich, Acros, or TCI and used without
further purification. Dichloromethane was dried (CaCl2), distilled
from CaH2, and stored over molecular sieves. Other commercial
grade solvents were distilled, and then stored over molecular
sieves. The drying agent employed was anhydrous MgSO4.
4
6a'
Entry
Additive
Time (h)
Yieldb (%)
eec (%)
1
None
None
None
Benzoic acid
Benzoic acid
Benzoic acid + H2O
AcOH
TFA
Phenyl glycine
(S)-1,10-Bi-2-naphthol
DMAP
0.5
1
3
0.5
3
1
1.5
24
4.5
24
24
24
99
92
90
97
98
99
95
<5
95
75
<5
73
94
91
89
93
93
91
87
n.d.
92
90
n.d.
62
2d
3e
4
5f
6
7
8
9
10
11
12
DABCO
a
Unless otherwise specified, all reactions were carried out with aldehyde 4
(0.40 mmol), N-phenylmaleimide (0.20 mmol), the catalyst (0.02 mmol), and
additive (0.02 mmol) in CH2Cl2 (0.5 mL).
5
b
Isolated yields after column chromatography on SiO2.
Determined by chiral HPLC analysis (Chiralcel OD-H).
5 mol % catalyst used.
2 mol % catalyst used.
c
d
e
f
Reaction performed at 4 °C.
the position and the electronic properties of the substituents on
the aromatic rings of the maleimides had a limited influence on
the stereoselectivity of the conjugate additions.
4.2. Synthesis of catalysts
We next investigated the catalytic efficiency of a simpler pri-
mary amine–thiourea 3c in order to confirm the role of the achiral
Chiral catalysts 3a–3c were synthesized by following the litera-
ture procedure.16

1446
M. Durmaz, A. Sirit / Tetrahedron: Asymmetry 24 (2013) 1443–1448
Table 3
Scope of 3a and 3b promoted enantioselective conjugate addition reactions of aldehydes with maleimidesa
O
N
O
O
O
3a 3b
or
(10 mol%)
R1
*
Ph
+
N
R
H
H
CH2Cl2, rt
R2 R1
R2
R2
O
O
Entry
R1
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4-NO2C6H4
Bn
4-ClC6H4
4-BrC6H4
C6H5
Bn
C6H5
Bn
4-BrC6H4
4-NO2C6H4
4-ClC6H4
C6H5
4-BrC6H4
Bn
4-NO2C6H4
4-ClC6H4
C6H5
6b/6b0
6c/6c0
6d/6d0
6e/6e0
6f/6f0
96/98
99/99
81/84
99/94
74/72
79/84
95/91
90/94
61/64
92/88
86/82
88/91
59/57
85/86
90/87
55/62
61/63
88/90
89/92
84/86
88/87
86/89
90/92
91/93
94/98
84/87
83/87
88/92
77/87
84/90
89/93
76/81
81/80
90/94 (1.2:1)d
–CH2(CH2)3CH2–
–CH2(CH2)3CH2–
–CH2(CH2)2CH2–
–CH2(CH2)2CH2–
–CH2(CH2)2CH2–
–CH2(CH2)2CH2–
–CH2(CH2)2CH2–
C2H5
C2H5
C2H5
C2H5
C2H5
6g/6g0
6h/6h0
6i/6i0
9
6j/6j0
6k/6k0
6l/6l0
6m/6m0
6n/6n0
6o/6o0
6p/6p0
6q/6q0
6r/6r0
10
11
12
13
14
15
16
17
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CH3(CH2)2
a
b
c
Unless otherwise specified, all reactions were carried out with aldehyde (0.40 mmol), maleimide (0.20 mmol), and the catalyst (0.02 mmol) in CH2Cl2 (0.5 mL).
Isolated yields after column chromatography on SiO2.
Determined by chiral HPLC analysis (Chiralcel OD-H, AD-H or AS-H).
d
Diastereomeric ratio given in parentheses.
4.3. Representative procedure for the Michael addition
In typical experiment, -disubstituted aldehyde
4.3.5. (S)-2-(1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
5i
methylpropanal 6e0
a
a,a
½
a 2D5
ꢁ
¼ ꢂ3:1 (c 0.9, CHCl3); Enantiomeric excess: 87%, determined
(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,
15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room tem-
perature until the maleimide was consumed (monitored by TLC).
The corresponding product was obtained after column chromatog-
raphy (silica gel, eluent n-hexane/EtOAc). The enantiomeric excess
of the products was determined by chiral HPLC analysis using chiral
columns. All products were identified by spectroscopic data. Race-
mic samples of the Michael adducts were prepared using racemic
catalyst. Compounds 6a0–6i0, 6m0 and 6r0 are known. The analytical
and spectroscopic data are in accordance with those reported.
by chiral HPLC analysis (Chiralpak OD-H, hexane/iPrOH = 75/25,
0.6 mL/min, k = 254 nm), tR (major) = 30.8 min, tR (minor) = 54.2 min.
4.3.6. (S)-1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclohexanecarb-
5i
aldehyde 6f0
½
a 2D5
ꢁ
¼ ꢂ0:7 (c 0.8, CHCl3); Enantiomeric excess: 89%, determined
by chiral HPLC analysis (Chiralpak OD-H, hexane/iPrOH = 75/25,
0.6 mL/min, k = 254 nm), tR (major) = 33.1 min, tR (minor) = 44.3 min.
4.3.7. (S)-1-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)cyclohexanecarb-
5e
aldehyde 6g0
4.3.1. (S)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpropanal
½
a 2D5
ꢁ
¼ þ1:6 (c 0.9, CHCl3); Enantiomeric excess: 92%, determined
5a,b
6a0
by chiral HPLC analysis (Chiralpak AD-H, hexane/iPrOH = 80/20,
½
a 2D5
ꢁ
¼ ꢂ3:2 (c 0.8, CHCl3); Enantiomeric excess: 95%, determined
0.6 mL/min, k = 254 nm), tR (major) = 16.9 min, tR (minor) = 26.6 min.
by chiral HPLC analysis (Chiralpak OD-H, hexane/iPrOH = 75/25,
0.7 mL/min, k = 210 nm), tR (major) = 20.2 min, tR (minor) = 26.3 min.
4.3.8. (S)-1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclopentanecarb-
5a
aldehyde 6h0
4.3.2. (S)-2-Methyl-2-(1-(4-nitrophenyl)-2,5-dioxopyrrolidin-3-
½
a 2D5
ꢁ
¼ þ18:2 (c 1.0, CHCl3); Enantiomeric excess: 93%, determined
5a
yl)propanal 6b0
by chiral HPLC analysis (Chiralpak OD-H, hexane/iPrOH = 75/25,
½
a 2D5
ꢁ
¼ ꢂ2:9 (c 0.9, CHCl3); Enantiomeric excess: 90%, determined
0.5 mL/min, k = 254 nm), tR (major) = 43.2 min, tR (minor) = 62.9 min.
by chiral HPLC analysis (Chiralpak OD-H, hexane/iPrOH = 80/20,
1.0 mL/min, k = 254 nm), tR (major) = 56.6 min, tR (minor) = 71.7 min.
4.3.9. (S)-1-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)cyclopentanecarb-
5h
aldehyde 6i0
4.3.3. (S)-2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
½
a 2D5
ꢁ
¼ ꢂ0:7 (c 0.5, CHCl3); Enantiomeric excess: 98%, determined
5a,b
6c0
by chiral HPLC analysis (Chiralpak OD-H, hexane/iPrOH = 92/8,
½
a 2D5
ꢁ
¼ þ11:6 (c 0.8, CHCl3); Enantiomeric excess: 92%, determined
0.6 mL/min, k = 254 nm), tR (major) = 25.0 min, tR (minor) = 28.6 min.
by chiral HPLC analysis (Chiralpak AD-H, hexane/iPrOH = 80/20,
0.6 mL/min, k = 254 nm), tR (major) = 15.5 min, tR (minor) = 34.8 min.
4.3.10. (S)-1-(1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)cyclop-
entanecarbaldehyde 6j0
4.3.4. (S)-2-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
White solid; ½a 2D5
ꢁ
¼ þ1:9 (c 0.6, CHCl3); 1H NMR (400 MHz,
5b
methylpropanal 6d0
CDCl3): d = 1.68–1.74 (m, 1H), 1.77–1.88 (m, 4H), 2.01–2.11 (m,
2H), 2.31–2.38 (m, 1H), 2.50–2.59 (m, 1H), 2.90–3.00 (m, 2H),
7.18–7.22 (m, 2H), 7.56–7.60 (m, 2H), 9.35 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3): d = 25.7, 25.8, 32.4, 32.7, 33.2, 43.2, 60.2,
½
a 2D5
ꢁ
¼ ꢂ2:4 (c 1.0, CHCl3); Enantiomeric excess: 86%, determined
by chiral HPLC analysis (Chiralpak OD-H, hexane/iPrOH = 75/25,
0.6 mL/min, k = 254 nm), tR (major) = 30.4 min, tR (minor) = 56.7 min.

M. Durmaz, A. Sirit / Tetrahedron: Asymmetry 24 (2013) 1443–1448
1447
122.5, 128.3, 131.2, 132.3, 174.6, 177.4, 201.9 ppm; IR (cm–1) : 719,
763, 826, 926, 961, 1014, 1069, 1099, 1180, 1276, 1298, 1383,
1452, 1490, 1703, 1777, 2728, 2870, 2957; Anal. Calcd (%) for
1.69–1.86 (m, 3H), 2.48–2.54 (dd, J = 5.7, 18.4 Hz, 1H), 2.75–2.82
(dd, J = 9.4, 18.4 Hz, 1H), 3.08–3.12 (dd, J = 5.8, 9.4 Hz, 1H), 4.59–
4.67 (dd, J = 14.1, 17.2 Hz, 2H), 7.23–7.31 (m, 3H), 7.34–7.37 (m,
2H), 9.55 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): d = 8.5, 8.7,
24.1, 25.5, 32.3, 42.4, 43.5, 51.5, 127.9, 128.6, 128.9, 135.6, 175.7,
C16H16BrNO3 (350.21): C, 54.87; H, 4.61; N, 4.00. Found (%): C,
54.96; H, 4.77; N, 3.91. Enantiomeric excess: 87%, determined by
chiral HPLC analysis (Chiralpak OD-H, hexane/iPrOH = 70/30, 1.0 mL/
min, k = 254 nm), tR (major) = 16.3 min, tR (minor) = 36.7 min.
177.7, 179.6, 204.0 ppm; IR (cm–1):
m 705, 759, 796, 931, 1084,
1167, 1293, 1314, 1342, 1397, 1431, 1456, 1497, 1586, 1605,
1694, 1773, 2883, 2942, 2971; Anal. Calcd (%) for C17H21NO3
(287.35): C, 71.06; H, 7.37; N, 4.87. Found (%): C, 70.92; H, 7.20;
N, 4.98. Enantiomeric excess: 93%, determined by chiral HPLC anal-
4.3.11. (S)-1-(1-(4-Nitrophenyl)-2,5-dioxopyrrolidin-3-yl)cyclopentane-
carbaldehyde 6k0
Light brown solid; ½a D25
ꢁ
¼ þ2:3 (c 0.8, CHCl3); 1H NMR (400 MHz,
ysis
(Chiralpak
AS-H,
hexane/EtOH = 90/10,
0.7 mL/min,
CDCl3): d = 1.68–1.75 (m, 1H), 1.79–1.89 (m, 4H), 2.03–2.12 (m, 2H),
2.36–2.43 (m, 1H), 2.54–2.62 (m, 1H), 2.94–3.02 (m, 2H), 7.55–7.59
(m, 2H), 8.29–8.33 (m, 2H), 9.33 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3): d = 25.6, 25.7, 32.7, 32.9, 33.4, 43.2, 60.5, 124.4, 127.3,
137.8, 147.1, 174.1, 177.0, 202.0 ppm; IR (cm–1) : 689, 716, 749,
811, 854, 1110, 1175, 1298, 1344, 1378, 1452, 1498, 1597, 1712,
1779, 2727, 2872, 2957; Anal. Calcd (%) for C16H16N2O5 (316.31):
C, 60.75; H, 5.10; N, 8.86. Found (%): C, 60.86; H, 5.24; N, 8.72.
Enantiomeric excess: 87%, determined by chiral HPLC analysis
(Chiralpak OD-H, hexane/iPrOH = 65/35, 1.0 mL/min, k = 254 nm),
tR (major) = 24.5 min, tR (minor) = 49.9 min.
k = 254 nm), tR (minor) = 20.9 min, tR (major) = 23.2 min.
4.3.16. (S)-2-Ethyl-2-(1-(4-Nitrophenyl)-2,5-dioxopyrrolidin-3-
yl)butanal 6p0
White solid; ½a 2D5
ꢁ
¼ ꢂ1:7 (c 0.6, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 1.02 (q, J = 7.7 Hz, 6H), 1.69 (sextet, J = 7.5 Hz, 1H),
1.86–1.99 (m, 2H), 2.06 (sextet, J = 7.5 Hz, 1H), 2.66–2.73 (dd,
J = 6.0, 18.5 Hz, 1H), 2.94–3.01 (dd, J = 9.6, 18.4 Hz, 1H), 3.16–3.20
(dd, J = 6.0, 9.6 Hz, 1H), 7.54–7.57 (m, 2H), 8.29–8.33 (m, 2H),
9.59 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): d = 8.0, 23.3, 24.1,
32.0, 41.9, 55.0, 124.4, 127.1, 137.5, 147.1, 174.1, 176.6,
204.2 ppm; IR (cm–1):
m 715, 749, 794, 854, 931, 1110, 1172,
4.3.12. (S)-1-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)cyclop-
1298, 1344, 1378, 1459, 1498, 1524, 1597, 1612, 1714, 1780,
2885, 2941, 2973; Anal. Calcd (%) for C16H18N2O5 (318.32): C,
60.37; H, 5.70; N, 8.80. Found (%): C, 60.12; H, 5.84; N, 8.68.
Enantiomeric excess: 81%, determined by chiral HPLC analysis
(Chiralpak AS-H, hexane/EtOH = 75/25, 0.9 mL/min, k = 254 nm),
tR (minor) = 18.8 min, tR (major) = 22.5 min.
entanecarbaldehyde 6l0
White solid; ½a 2D5
ꢁ
¼ þ1:1 (c 0.8, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 1.68–1.74 (m, 1H), 1.77–1.87 (m, 4H), 2.01–2.11 (m,
2H), 2.30–2.37 (m, 1H), 2.50–2.59 (m, 1H), 2.90–3.00 (m, 2H),
7.24–7.28 (m, 2H), 7.41–7.44 (m, 2H), 9.35 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3): d = 25.7, 25.8, 32.4, 32.8, 33.2, 43.2, 60.2,
128.0, 129.4, 130.6, 134.4, 174.7, 177.5, 201.9 ppm; IR (cm–1) :
730, 770, 812, 830, 927, 1017, 1092, 1181, 1277, 1385, 1451,
1493, 1704, 1777, 2727, 2871, 2957; Anal. Calcd (%) for C16H16-
ClNO3 (305.76): C, 62.85; H, 5.27; N, 4.58. Found (%): C, 62.63; H,
5.39; N, 4.42. Enantiomeric excess: 92%, determined by chiral HPLC
analysis (Chiralpak OD-H, hexane/iPrOH = 70/30, 1.0 mL/min,
k = 254 nm), tR (major) = 16.7 min, tR (minor) = 39.7 min.
4.3.17. (S)-2-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
ethylbutanal 6q0
Light yellow solid;
½
a 2D5
ꢁ
¼ ꢂ1:9 (c 0.7, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 1.00 (q, J = 7.6 Hz, 6H), 1.70 (sextet,
J = 7.4 Hz, 1H), 1.82–2.05 (m, 3H), 2.63–2.70 (dd, J = 5.9, 18.4 Hz,
1H), 2.91–2.98 (dd, J = 9.6, 18.4 Hz, 1H), 3.18–3.22 (dd, J = 5.9,
9.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 9.60
(s, 1H) ppm; 13C NMR (100 MHz, CDCl3): d = 8.1 (d, J = 3.1 Hz),
23.3, 24.3, 31.8, 41.8, 54.7, 127.8, 129.4, 130.4, 134.5, 174.6,
177.0, 204.1 ppm; IR (cm–1) : 728, 770, 793, 830, 937, 1017,
1092, 1177, 1277, 1382, 1460, 1493, 1703, 1778, 2883, 2941,
2971; Anal. Calcd (%) for C16H18ClNO3 (307.77): C, 62.44; H, 5.89;
N, 4.55. Found (%): C, 62.32; H, 5.74; N, 4.41. Enantiomeric excess:
80%, determined by chiral HPLC analysis (Chiralpak AS-H, hexane/
EtOH = 85/15, 0.9 mL/min, k = 254 nm), tR (minor) = 16.1 min, tR
(major) = 18.8 min.
4.3.13. (S)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-ethylbutanal
5c,i
6m0
½
a 2D5
ꢁ
¼ ꢂ6:3 (c 1.0, CHCl3); Enantiomeric excess: 87%, deter-
mined by chiral HPLC analysis (Chiralpak AS-H, hexane/
EtOH = 70/30, 0.8 mL/min, k = 254 nm), tR (minor) = 13.2 min, tR
(major) = 16.4 min.
4.3.14. (S)-2-(1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
ethylbutanal 6n0
White solid; ½a 2D5
ꢁ
¼ ꢂ2:1 (c 0.9, CHCl3); 1H NMR (400 MHz,
4.3.18. (S)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpentanal
5c
CDCl3): d = 0.99 (q, J = 7.6 Hz, 6H), 1.70 (sextet, J = 7.5 Hz, 1H),
1.82–2.05 (m, 3H), 2.63–2.69 (dd, J = 5.9, 18.4 Hz, 1H), 2.91–2.98
(dd, J = 9.6, 18.4 Hz, 1H), 3.17–3.21 (dd, J = 5.9, 9.6 Hz, 1H), 7.16–
7.19 (m, 2H), 7.56–7.60 (m, 2H), 9.60 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3): d = 8.1 (d, J = 3.0 Hz), 23.3, 24.2, 31.8, 41.8,
54.7, 122.5, 128.1, 130.9, 132.4, 174.6, 177.0, 204.1 ppm; IR
6r0
½
a 2D5
ꢁ
¼ ꢂ1:3 (c 0.6, CHCl3); Enantiomeric excess: 94%, determined
by chiral HPLC analysis (Chiralpak AS-H, hexane/EtOH = 80/20,
0.8 mL/min, k = 254 nm), tR (minor1) = 12.1 min, tR (major1) =
13.5 min, tR (major2) = 17.3 min, tR (minor2) = 21.4 min.
(cm–1) :
m
664, 685, 711, 754, 793, 825, 935, 1069, 1174, 1288,
Acknowledgements
1318, 1381, 1451, 1490, 1584, 1603, 1706, 1779, 2881, 2941,
2969; Anal. Calcd (%) for C16H18BrNO3 (352.22): C, 54.56; H, 5.15;
N, 3.98. Found (%): C, 54.18; H, 5.32; N, 3.76%. Enantiomeric excess:
90%, determined by chiral HPLC analysis (Chiralpak AS-H, hexane/
EtOH = 70/30, 0.8 mL/min, k = 254 nm), tR (minor) = 19.8 min, tR
(major) = 23.4 min.
We gratefully acknowledge financial support from the Scientific
and Technological Research Council of Turkey (TUBITAK) and the
Necmettin Erbakan University.
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