Highly enantioselective michael addition promoted by a new diterpene-derived bifunctional thiourea catalyst: A doubly stereocontrolled approach to chiral succinimide derivatives

Article abstract of DOI:10.1002/chir.22279

A doubly stereocontrolled organocatalytic asymmetric Michael addition to the synthesis of substituted succinimides is described. Starting from aldehydes and maleimides, both enantiomers of the succinimides could be obtained in high to excellent yields (up

Full text of DOI:10.1002/chir.22279

CHIRALITY 26:121–127 (2014)
Highly Enantioselective Michael Addition Promoted by a New
Diterpene-Derived Bifunctional Thiourea Catalyst: A Doubly
Stereocontrolled Approach to Chiral Succinimide Derivatives
1
ZHONG-TAI SONG,1 TAO ZHANG,1,2 HAI-LONG DU,1 ZHI-WEI MA,1 CHANG-HUA ZHANG,1 AND JING-CHAO TAO
1College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
2School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
*
ABSTRACT
A doubly stereocontrolled organocatalytic asymmetric Michael addition to the
synthesis of substituted succinimides is described. Starting from aldehydes and maleimides,
both enantiomers of the succinimides could be obtained in high to excellent yields (up to 98%)
and enantioselectivities (up to 99%) when one of the two special chiral diterpene-derived
bifunctional thioureas was individually used as a catalyst. Moreover, these catalysts can be effi-
ciently used in large-scale catalytic synthesis with the same level of yield and enantioselectivity.
Chirality 26:121–127, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: enantiomers; diterpene-derived thiourea; maleimide; Michael reaction; succinimide
INTRODUCTION
diterpene moiety (isosteviol) into the thiourea catalysts led to
impressive results in asymmetric reactions.31–37 Inspired by
the excellent chiral structural skeleton of isosteviol, we de-
signed and synthesized a new class of primary amine-thiourea
bifunctional catalysts 3a and 3b. With these novel catalysts in
hand, the effects of the thiourea catalysts were investigated.
Although there is still much to investigate in terms of the role
of the chiral terpene moiety in the stereocontrol that is exerted
by the bifunctional thiourea catalysts, we believe that this
excellent structural backbone is necessary. Based on this, excel-
lent results are expected when the catalyst is varied by moving
the thiourea moiety from 16-position to 4-position (Fig. 1).
We now report a highly efficient asymmetric Michael addi-
tion of aldehydes to maleimides promoted by new diterpene-
derived primary amine thioureas. Both enantiomers were
finished with high to excellent yields (up to 98%) and
enantioselectivities (up to 99%) and this catalytic system can
be used in large-scale reactions with the enantioselectivity
being maintained at the same level.
Substituted maleimides are important structural scaffolds
and other precursors of some biologically interesting sub-
stances. The chiral α-substituted succinimides are prevalent
in a variety of natural products and some clinical drug candi-
dates.1–5 Since the report of Komura and co-workers in 1987,
on the isolation of andrimid as a new and highly specific
antibiotic,2 a great deal of effort has been dedicated to the
discovery and synthesis of chiral succinimides. Notably,
organocatalytic versions using maleimides as substrates for
the synthesis of chiral succinimides have been actively
pursued recently.6–16 Maleimides are an important class of
substrates, which have successfully been used in asymmet-
ric organocatalytic transformations such as asymmetric
cycloadditions, Michael reactions, and asymmetric cascade
reactions.7–16 Asymmetric organocatalytic functionalization
of maleimides provides easy access to chiral-substituted
succinimide derivatives.
Michael addition is one of the most efficient and powerful
atom-economical carbon-carbon bond-forming reactions in
synthetic chemistry.17–20 In particular, the asymmetric Michael
addition of maleimide represents a potentially attractive
approach, which opens up efficient direct entries to substituted
succinimides from simple precursors.7–16
Both enantiomers of a chiral compound are often useful
and versatile in terms of pharmaceutical industry and organic
synthesis.21,22 However, the efficient preparation of both
enantiomers of a chiral compound still represents a daunting
task, and to the best of our knowledge, effective double
asymmetric induction on metal-free organocatalytic reactions
have rarely been reported to date.23–26 Thus, the development
of an effective organocatalytic method to prepare both
enantiomers of substituted succinimides individually is a
highly desirable goal.
EXPERIMENTAL
All chemicals were used as received unless otherwise noted. Reagent
grade solvents were redistilled prior to use. 1H nuclear magnetic
resonance (NMR) and 13C NMR spectra were collected on a Bruker
DPX 400 NMR spectrometer with tetramethylsilane (TMS) as internal
reference. Infrared (IR) spectra were determined on a Thermo Nicolet
IR200 unit. High-resolution mass spectra (HRMS) were obtained on a
Waters Micromass Q-Tof Micro instrument using the electrospray
ionization (ESI) technique. Chromatography was performed on silica
gel (200–300 mesh). Melting points were determined using the aXT5
apparatus and are uncorrected. Optical rotations were determined on a
Perkin Elmer 341 polarimeter. Enantiomeric excess was determined by
chiral HPLC at room temperature using Labtech 2006 pump equipped
with Labtech UV600 ultra detector with Chiral columns.
Thiourea-based catalysts are considered powerful and efficient
catalysts for various types of asymmetric reactions, and great
progress has been achieved in this field.27–30 Nevertheless, the
skeleton structures to construct thiourea catalysts are very
limited, and there is still great demand for novel bifunctional
thiourea catalysts for this purpose. Recently, we found that,
similar to the cinchona alkaloids, the incorporation of a chiral
*Correspondence to: J.-C. Tao, College of Chemistry and Molecular Engineering,
Zhengzhou University, Zhengzhou, Henan, People’s Republic of China. E-mail:
jctao@zzu.edu.cn
Received for publication 13 July 2013; Accepted 17 November 2013
DOI: 10.1002/chir.22279
Published online 14 January 2014 in Wiley Online Library
(wileyonlinelibrary.com).
© 2014 Wiley Periodicals, Inc.

122
SONG ET AL.
General Procedure for the Michael Addition
The aldehyde (4, 0.40 mmol) was added to a mixture of catalyst 3 (1
mol%) and corresponding maleimide 5 (0.20 mmol) in toluene (1.0 mL).
The reaction mixture was stirred at ambient temperature for the needed
time. After maleimide was consumed by thin-layer chromatography
(TLC) analysis, the reaction mixture was subjected to TLC on silica gel
(ethyl acetate/petroleum ether) to afford the pure Michael product. The
enantiomeric excess (ee) of the products was determined by chiral HPLC
analysis using Chiral columns.
Fig. 1. Design of novel diterpene-derived thiourea.
Characterization of Michael Addition Products
2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpropanal (6a).
35 1H NMR (400 MHz, CDCl3, TMS): δ 1.27 (s, 3H), 1.31 (s, 3H), 2.61
(dd, J = 5.6, 18.2 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.14 (dd, J = 5.6,
9.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.47 (t, J =
7.2 Hz, 2H), 9.50 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): δ 19.6,
20.3, 31.8, 45.0, 48.5, 126.5, 128.7, 129.2, 131.8, 174.8, 176.9, 202.8; IR (KBr,
cm-1): ν 499, 563, 627, 666, 703, 755, 814, 885, 1164, 1189, 1395, 1454 ,1471,
1490, 1500, 1705, 1773, 2730, 2822, 2932, 2989, 3459; HPLC: Chiralcel OD-H
(Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 25.1 min
(major), 31.8 min (minor).
Synthesis of Catalyst
Synthesis of isosteviolisothiocyanate (2). Ethanol (5 mL) was added
to isosteviol amine (1, 1.28 g, 4.4 mmol), CS2 (3.34 g, 44 mmol), and Et3N
(0.44 g, 4.4 mmol) were added while stirring, resulting in the precipitation
of the dithiocarbamate. The reaction mixture was stirred for 30 min
at room temperature and then cooled in an ice bath. Boc2O (0.95 g,
4.4 mmol), dissolved in ethanol (1 mL), was added followed by the
immediate addition of a catalytic amount of DMAP (2 mol %) in ethanol
(1 mL). The reaction mixture was kept in the ice bath for 5 min and was then
allowed to reach room temperature stirring for a further 5 min and evapo-
rated thoroughly in vacuo. After purification the isosteviol isothiocyanate
2 was obtained as a white solid.
Yield: 89%; ½αꢀD = -96.6 (c 1.0, CH2Cl2); Mp.: 125.2-126.5 C; IR (KBr, cm ):
2926, 2849, 2263, 2107, 1735, 1449, 1374, 1251, 1188, 975, 911; 1H NMR
(400 MHz, CDCl3, TMS): δ 2.66 (dd, J = 18.4, 3.6 Hz, 1H), 1.86-1.89 (m, 1H),
1.78 (m, 1H), 1.74 (m, 1H), 1.68-1.70 (m, 2H), 1.63-1.65 (m, 3H), 1.50-1.53
(m, 2H), 1.47 (s, 2H), 1.38 (s, 3H), 1.31-1.35 (m, 3H), 1.13-1.22 (m, 4H,
0.98-1.00(m, 1H), 0.95 (s, 3H), 0.91 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 221.9, 130.2, 61.9, 59.1, 55.2, 54.6, 54.4, 48.8, 48.7, 40.5, 40.2, 39.1, 38.1,
37.4, 37.0, 30.4, 19.9, 19.8, 17.9, 13.8
2-(1-(4-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
(6b). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.29 (s, 3H), 1.36(s, 3H),
2.61 (dd, J = 5.6, 18.4 Hz, 1H), 2.98 (dd, J = 9.6, 18.4 Hz, 1H), 3.12 (dd, J =
5.6, 9.6 Hz, 1H), 7.16 (m, 2H), 7.27 (m, 2H), 9.49 (s, 1H); 13C NMR (100
MHz, CDCl3, TMS): δ 19.9, 20.5, 31.9, 44.9, 48.7, 116.2, 127.7, 128.4,
163.5, 174.7, 176.9, 202.8; IR (KBr, cm-1): ν 468, 532, 669, 760, 841,
1198, 1222, 1392, 1508, 1703, 1728, 1780, 2977, 3081, 3121, 3464; HPLC:
Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ =
220 nm): tR = 24.2 min (major), 41.0 min (minor).
o
-1
20
2-(1-(3-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
(6c). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.26 (s, 3H), 1.33(s, 3H),
2.60 (dd, J = 5.6, 18.4 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.12 (dd, J
= 5.6, 9.6 Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H), 7.33-7.42 (m, 3H), 9.48 (s,
1H); 13C NMR (100 MHz, CDCl3, TMS): δ 19.7, 20.4, 31.8, 44.9, 48.6,
124.8, 126.8, 128.8, 130.1, 133.0, 134.5, 174.4, 176.6, 202.8; IR (KBr, cm-
1): ν 481, 582, 624, 683, 731, 791, 808, 873, 964, 1073, 1155, 1193, 1386,
1430, 1477, 1585, 1705, 1778, 2850, 2919, 2969, 3467; HPLC: Chiralcel
OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm):
tR = 22.5 min (major), 27.5 min (minor).
Synthesis of isosteviolthiourea (3). Isosteviolisothiocyanate (2, 0.99
g, 3 mmol) was added over a period of 0.5 h to a stirred solution of (R,
R)- or (S,S)-1,2-diaminocyclohexane (0.41 g, 3.6 mmol) in dry
dichloromethane (25 mL). The reaction mixture was stirred for a further
12 h at room temperature. The solvent was removed under reduced pres-
sure and the crude product was purified using column chromatography
eluting with CHCl3/MeOH = 50:1. Isosteviol thiourea 3 was obtained as
a white solid.
3a: Yield: 72%; ½αꢀ2D0= -34.2 (c 1.0, CH2Cl2); Mp.:136.2-137.4oC; IR (KBr,
cm-1): 3380, 3223, 3042, 2930, 2853, 1733, 1631, 1533, 1451, 1364,
1320, 969; 1H NMR (400 MHz, CDCl3, TMS): δ 4.73 (s, 2H), 3.0
(s, 1H), 2.67 (m, 1H), 2.10 (m, 2H), 1.76-1.86(m, 5H), 1.67-1.71
(m, 4H), 1.57-1.59 (m, 7H), 1.41-1.44 (m, 5H), 1.29-1.31 (m, 2H),
1.23-1.26 (m, 3H), 1.09-1.14 (m, 5H), 0.99 (s, 3H), 0.90-0.93 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 223.1, 180.8, 58.4, 57.9, 55.6, 55.1,
54.2, 48.8, 41.0, 39.2, 37.7, 37.2, 32.0, 31.1, 26.9, 24.5, 24.3, 19.8,
19.1, 17.6, 15.2; HRMS (ESI, m/z) calcd. for C26H43N3OS [M+H]+
446.3205. Found: 446.3206.
2-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
(6d). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.28 (s, 3H), 1.35(s, 3H), 2.61
(dd, J = 5.2, 18.4 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.11 (dd, J = 5.6, 9.6
Hz, 1H), 7.24 (m, 2H), 7.43 (m, 2H), 9.49 (s, 1H); 13C NMR (100 MHz,
CDCl3, TMS): δ 19.9, 20.5, 32.0, 45.0, 48.7, 127.8, 129.4, 130.3, 134.5,
174.5, 176.7, 202.7; IR (KBr, cm-1): ν 510, 730, 773, 838, 1090, 1167, 1200,
1398, 1493, 1702, 1720, 1773, 2969, 3456; HPLC: Chiralcel OD-H (Hex-
anes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 25.2 min
(major), 45.9 min (minor).
3b: Yield: 75%; ½αꢀ2D0 = -65.8 (c 1.0, CH2Cl2); Mp.:144.2-145.1oC; IR
2-(1-(3-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
(6e). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.29 (s, 3H), 1.36(s, 3H),
2.62 (dd, J = 5.6, 18.4 Hz, 1H), 2.98 (dd, J = 9.6, 18.4 Hz, 1H), 3.11
(dd, J = 5.6, 9.6 Hz, 1H), 7.24-7.27 (m, 1H), 7.32-7.36 (t, J = 8.0 Hz, 1H),
7.47-7.48 (t, J = 2.0 Hz, 1H), 7.52-7.55 (m, 1H), 9.49 (s, 1H); 13C NMR (100
MHz, CDCl3, TMS): δ 19.9, 20.5, 32.0, 45.0, 48.7, 122.5, 125.3, 129.6, 130.4,
131.8, 133.0, 174.7, 176.6, 202.7; IR (KBr, cm-1): ν 621, 661, 681, 721, 785,
814, 886, 1066, 1180, 1383, 1425, 1475, 1573, 1706, 1778, 2850, 2919, 2963,
3466; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min,
λ = 220 nm): tR = 24.5 min (major), 30.2 min (minor).
(KBr, cm-1): 3363, 3228, 3046, 2931, 2851, 1736, 1629, 1536, 1452, 1369,
1
1315, 1280, 1247, 975; H NMR (400 MHz, CDCl3, ppm): δ 6.21 (s, 1H),
4.42 (s, 1H), 3.54 (s, 1H), 3.15-3.19 (m, 1H), 2.68-2.73(m, 1H), 2.09-2.28
(m, 2H), 1.75-1.87 (m, 5H), 1.63-1.70 (m, 4H), 1.57-1.59 (m, 8H), 1.39-
1.43 (m, 4H), 1.25-1.34 (m, 4H), 1.22 (s, 3H), 1.02-1.08 (m, 5H), 0.98
(s, 3H), 0.89-0.92 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 223.1, 180.8,
58.5, 57.9, 55.6, 55.2, 54.2, 48.8, 41.0, 39.2, 37.7, 37.2, 32.0, 31.1, 27.0,
24.4, 24.3, 19.8, 19.1, 17.6, 15.2; HRMS (ESI, m/z) calcd. for C26H43N3OS
[M+H]+ 446.3205. Found: 446.3203.
Chirality DOI 10.1002/chir

THIOUREA CATALYZED ENANTIOSELECTIVE MICHAEL ADDITION
123
2-(1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
(6f). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.28 (s, 3H), 1.36 (s, 3H),
2.61 (dd, J = 5.6, 18.0 Hz, 1H), 2.97 (dd, J = 9.6, 18.4 Hz, 1H), 3.11
(dd, J = 5.6, 9.6 Hz, 1H), 7.17-7.21 (m, 2H), 7.58-7.61 (m, 2H), 9.48 (s, 1H);
13C NMR (100 MHz, CDCl3, TMS): δ 19.9, 20.5, 32.0, 45.0, 48.7, 122.6,
128.1, 130.8, 132.4, 174.4, 176.6, 202.7; IR (KBr, cm-1): ν 570, 720, 769, 828,
887, 1015, 1067, 1168, 1200, 1399, 1489, 1698, 1719, 1770, 2849, 2922,
2966, 3093, 3450; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25,
flow rate = 0.6 mL/min, λ = 220 nm): tR = 32.4 min (major), 55.3
min (minor).
PrOH = 80/20, flow rate = 0.6 mL/min, λ = 220 nm): tR = 59.8 min (major),
74.2 min (minor).
35
2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal (6l).
1H
NMR (400 MHz, CDCl3, TMS): δ 1.15 (d, 6H), 2.45 (dd, J = 5.6, 18.4 Hz,
1H), 2.81 (dd, J = 9.2, 18.4 Hz, 1H), 3.03 (dd, J = 5.6, 9.2 Hz, 1H), 7.24-7.37
(m, 5H), 9.48 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): δ 19.0, 21.0,
31.4, 42.4, 44.9, 48.0, 128.0, 128.6, 128.7, 135.7, 175.4, 177.5, 202.7; IR
(KBr, cm-1): ν 668, 708, 895, 1084, 1171, 1345, 1400, 1431, 1456, 1497,
1701, 1729, 1774, 2932, 2968, 3446; HPLC: Chiralpak AD-H
(Hexanes/i-PrOH = 80/20, flow rate = 0.6 mL/min, λ = 220 nm): tR
13.2 min (major), 28.1 min (minor).
=
2-Methyl-2-(1-(3-nitrophenyl)-2,5-dioxopyrrolidin-3-yl)propanal
(6g). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.32 (s, 3H), 1.42(s, 3H),
2.67 (dd, J = 5.6, 18.4 Hz, 1H), 2.03 (dd, J = 9.6, 18.4 Hz, 1H), 3.13 (dd, J
= 5.6, 9.6 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.71 (dt, J = 1.6, 8.0 Hz, 1H),
8.25-8.28 (m, 2H), 9.48 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): δ
20.3, 20.7, 32.1, 45.0, 49.0, 121.9, 123.3, 129.9, 132.5, 132.9, 148.5,
174.0, 176.4, 202.7; IR (KBr, cm-1): ν 581, 679, 731, 782, 820, 1193,
1350, 1395, 1481, 1529, 1587, 1712, 1780, 2733, 2833, 2874, 2937,
2970, 3097, 3473; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25,
flow rate = 0.6 mL/min, λ = 220 nm): tR = 31.7 min (major), 38.3 min
(minor).
1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclohexanecarbaldehyde
35
(7a).
1H NMR (CDCl3, 400 MHz) δ 1.54-1.63 (m, 7H), 1.85 (d,
J=8.8 Hz, 1H), 1.96 (s, 2H), 2.64-2.68 (m, 1H), 2.86 (dd, J=9.6, 16.0
Hz, 1H), 3.21 (m, 1H), 7.27-7.29 (m, 2H), 7.39-7.48 (m, 3H), 9.53 (s,
1H); 13C NMR (100 MHz, CDCl3, TMS) δ 21.2, 21.4, 25.1, 28.1, 28.6,
31.6, 42.7, 52.2, 126.6, 128.7, 129.2, 131.9, 174.8, 177.1, 204.6; IR
(KBr, cm-1): ν 627, 658, 699, 762, 1159, 1186, 1214, 1397, 1499, 1705,
1772, 2857, 2933, 3447; HPLC: Chiralcel OD-H (Hexanes/i-PrOH =
75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 30.2 min (major),
38.9 min (minor).
2-Methyl-2-(1-(4-nitrophenyl)-2,5-dioxopyrrolidin-3-yl)propanal
(6h). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.32 (s, 3H), 1.43(s, 3H),
2.67 (dd, J = 5.6, 18.0 Hz, 1H), 3.02 (dd, J = 9.6, 18.0 Hz, 1H), 3.11 (dd, J =
5.6, 9.6 Hz, 1H), 7.58 (dt, J = 2.4, 9.2 Hz, 2H), 8.34 (dt, J = 1.6, 9.2 Hz,
2H), 9.47 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): δ 20.4, 20.8,
32.2, 45.0, 49.0, 124.4, 127.1, 137.4, 147.1, 173.9, 176.2, 202.7; IR (KBr,
cm-1): ν 585, 644, 689, 718, 752, 782, 852, 1171, 1200, 1292, 1347, 1396,
1494, 1524, 1593, 1611, 1709, 1778, 2860, 2968, 3116, 3473; HPLC:
Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ =
220 nm): tR = 50.5 min (major), 64.8min (minor).
1-(1-(4-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)cyclohexanecarbaldehyde
(7b). 35 1H NMR (CDCl3, 400 MHz) δ 1.54-1.68 (m, 7H), 1.83-1.86 (m, 1H),
1.90-1.97 (m, 2H), 2.01-2.08 (m, 1H), 2.66 (dd, J = 6.0, 18.0 Hz, 1H), 2.87 (dd, J
= 9.6, 18.0 Hz, 1H), 3.22 (dd, J = 6.0, 9.6 Hz, 1H), 7.12-7.18 (m, 2H), 7.25-7.31
(m, 2H), 9.51 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 21.1, 21.3, 25.1,
28.2, 28.5, 31.6, 42.2, 52.4, 116.1, 116.3, 127.8, 127.9, 128.5, 174.7, 177.1, 204.5; IR
-1
(KBr, cm ): ν 528, 594, 654, 754, 772, 843, 878, 948, 1095, 1181, 1220, 1296,
1394, 1449, 1511, 1600, 1704, 1775, 2854, 2945, 3076, 3465; HPLC: Chiralcel OD-H
(Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 33.7 min (major),
58.2 min (minor).
2-(2,5-Dioxo-1-(p-tolyl)pyrrolidin-3-yl)-2-methylpropanal (6i). 35 1H
NMR (400 MHz, CDCl3, TMS): δ 1.28 (s, 3H), 1.31(s, 3H), 2.38 (s, 3H), 2.60
(dd, J = 5.2, 18.4 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.16 (dd, J = 5.6,
9.6 Hz, 1H), 7.14 (m, 2H), 7.26 (m, 2H), 9.52 (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS): δ 19.6, 20.3, 21.2, 31.8, 45.0, 48.5, 126.3,
129.1, 129.9, 138.8, 174.9, 177.0, 202.8; IR (KBr, cm-1): ν 510, 669,
754, 782, 822, 1167, 1202, 1397, 1512, 1708, 1732, 1779, 2929, 2964,
3465; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate =
0.6 mL/min, λ = 220 nm): tR = 24.9 min (major), 30.3 min (minor).
1-(2,5-Dioxo-1-(p-tolyl)pyrrolidin-3-yl)cyclohexanecarbaldehyde
(7i). 35 1H NMR (CDCl3, 400 MHz) δ 1.49-1.63 (m, 7H), 1.83-1.89 (m,
1H), 1.94-1.95 (m, 2H), 2.37 (s, 3H), 2.66 (dd, J = 6.0, 18.4 Hz, 1H), 2.86
(dd, J = 9.6, 18.0 Hz, 1H), 3.20 (dd, J = 6.0, 9.6 Hz, 1H), 7.12-7.16 (m, 2H),
7.25-7.27 (m, 2H), 9.55 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ
21.2, 21.3, 21.5, 25.1, 28.1, 28.7, 31.5, 52.1, 126.3, 126.4, 129.2, 129.8,
138.7, 175.0, 177.1, 204.6; IR (KBr, cm-1): ν 510, 671, 744, 818, 934,
1103, 1204, 1397, 1447, 1512, 1708, 1773, 2860, 2930, 3455; HPLC:
Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ
= 220 nm): tR = 31.9 min (major), 36.7 min (minor).
2-(1-(2,6-Dimethylphenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
(6j). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.30 (s, 3H), 1.35(s, 3H), 2.08
(s, 3H), 2.18 (s, 3H), 2.70 (dd, J = 6.4, 18.4 Hz, 1H), 3.01 (dd, J = 9.6, 18.4
Hz, 1H), 3.23 (dd, J = 6.4, 9.6 Hz, 1H), 7.12-7.15 (m, 2H), 7.21-7.26 (m,
1H), 9.53 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): δ 17.8, 18.0,
19.8, 20.5, 32.0, 45.5, 48.1, 128.5, 128.7, 129.5, 130.2, 135.5, 136.1,
174.5, 176.6, 202.7; IR (KBr, cm-1): ν 492, 665, 724, 746, 784, 864,
909, 1028, 1070, 1193, 1284, 1381, 1474, 1704, 1732, 1780, 2710,
2809, 2926, 2979, 3469; HPLC: Chiralcel OD-H (Hexanes/i-PrOH =
75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 20.0 min (major),
26.8 min (minor).
1-(1-(2-Methoxyphenyl)-2,5-dioxo-pyrrolidin-3-yl)cyclohexane-
35
carbaldehyde (7k).
1H NMR (CDCl3, 400 MHz) δ 1.45-1.70 (m,
7H), 1.85-2.01 (m, 3H), 2.66 (dd, J = 5.6, 18.0 Hz, 1H), 2.85 (dd, J = 9.6,
18.0 Hz, 1H), 3.18 (dd, J = 5.6, 9.2 Hz, 1H), 3.78 (s, 3H), 6.99-7.05 (m, 2H),
7.13 (dd, J = 8.0, 29.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 9.55 (s, 1H); 13C
NMR (100 MHz, CDCl3, TMS) δ 21.3, 22.3, 25.2, 28.1, 28.6, 29.7, 31.7,
52.0, 55.8, 112.0, 120.6, 120.9, 129.1, 130.8, 154.6, 174.8, 176.3, 204.7; IR
(KBr, cm-1): ν 471, 623, 675, 755, 1020, 1195, 1256, 1286, 1394, 1461, 1509,
1602, 1704, 1775, 2853, 2927, 3402; HPLC: AE.LICHROM-AM2-5 (Hex-
anes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 58.4 min
(major), 79.3 min (minor).
2-(1-(2-Methoxyphenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
(6k). 35 1H NMR (400 MHz, CDCl3, TMS): δ 1.28 (s, 3H), 1.30(s, 3H),
2.60 (dd, J = 5.6, 18.4 Hz, 1H), 2.98 (dd, J = 8.0, 18.0 Hz, 1H), 3.21 (dd,
J = 5.2, 9.6 Hz, 1H), 3.78 (s, 3H), 6.99-7.05 (m, 2H), 7.12 (q, J = 8.0 Hz,
1H), 7.39 (t, J = 8.0 Hz, 1H), 9.59 (s, 1H); 13C NMR (100 MHz, CDCl3,
TMS): δ 19.5, 20.3, 31.6, 45.2, 48.1, 55.7, 112.1, 120.6, 120.9, 129.1, 130.9,
154.6, 174.8, 176.7, 202.9; IR (KBr, cm-1): ν 472, 567, 623, 669, 756, 865,
1023, 1044, 1114, 1191, 1254, 1284, 1303, 1389, 1465, 1505, 1601, 1709,
1781, 2847, 2930, 2975, 3475; HPLC: AE.LICHROM-AM2-5 (Hexanes/i-
1-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)cyclohexanecarbaldehyde
(7l). 35 1H NMR (CDCl3, 400 MHz) δ 1.38-1.53 (m, 7H), 1.73-1.76
(m, 2H), 1.87-1.92 (m, 1H), 2.50 (dd, J = 5.6, 18.0 Hz, 1H), 2.68 (dd,
J = 9.2, 18.0 Hz, 1H), 3.03 (dd, J = 6.0, 8.8 Hz, 1H), 4.62 (dd, J = 14.4,
24.0 Hz, 2H), 7.24-7.36 (m, 5H), 9.49 (s, 1H); 13C NMR (100 MHz,
CDCl3, TMS) δ 21.3, 21.5, 25.0, 27.7, 28.7, 31.1, 42.3, 51.4, 127.8,
128.5, 135.7, 175.4, 177.5, 204.6; IR (KBr, cm-1): ν 706, 927, 1083,
Chirality DOI 10.1002/chir

124
SONG ET AL.
1169, 1343, 1399, 1431, 1454, 1697, 1773, 2854, 2934, 3450; HPLC:
Chiralpak AD-H (Hexanes/i-PrOH = 80/20, flow rate = 0.6 mL/min,
λ = 220 nm): tR = 14.1 min (major), 22.6 min (minor).
RESULTS AND DISCUSSION
With the novel diterpene-derived bifunctional thioureas 3a
and 3b in hand, we investigated the catalytic activities for
asymmetric Michael addition with isobutyraldehyde 4a as
the donor aldehyde and N-phenylmaleimide 5a as the accep-
tor substrate in chloroform at ambient temperature using
thiourea 3a as an organocatalyst (Table 1, entry 1). The
results indicated that the thiourea 3a can efficiently catalyze
this transformation with 82% yield and 87% ee (Scheme 1).
We then simply examined the effects of other solvents on the
reaction. Aprotic solvents such as toluene, 1,2-dichloroethane,
THF, and CHCl3 gave high to excellent yields (81–97%) and
enantioselectivities (82–95%, Table 1, entries 1–4). Changing
the solvent to protic solvent such as CH3OH, both the yield
and enantioselectivity were remarkably decreased (Table 1,
entry 5). In addition, the use of H2O only gave the adduct
moderate enantioselectivity (Table 1, entry 6). This was proba-
bly due to the disbenefit of hydrogen bonding interactions
between substrates and the protic solvents, which disturbed
the efficient aggregation surrounding the thiourea catalyst.
Having confirmed toluene as the optimum solvent for
the reaction, other factors were thoroughly investigated.
Adjusting the reaction temperature demonstrated a slight
influence on the yield and the enantioselectivity of the
reaction. Reducing the catalyst loading from 15 mol% to 1
mol% did not affect the yield but the enantioselectivity
increased obviously (Table 2, entries 1–4) , while almost
perfect stereocontrol was realized by employing 1 mol%
(Table 2, entry 4). When the catalyst was further lowered
35
2-(2,5-dioxo-1-phenylpyrrolidin-3-yl)hexanal (8a).
1H NMR
(400 MHz, CDCl3, TMS): δ 1.30 (t, J = 5.6 Hz, 3H), 1.26-1.34 (m, 4H),
1.60-1.66 (m, 2H), 2.63 (dd, J = 5.6, 18.4 Hz, 1H), 2.99 (dd, J = 9.6, 18.4
Hz, 1H), 3.16 (dd, J = 5.6, 9.6 Hz, 1H), 3.34 (dd, J = 8.8, 18.4 Hz, 1H),
7.27-7.33 (m, 2H), 7.38-7.51 (m, 3H), 9.52 (s, 1H); 13C NMR (100 MHz,
CDCl3, TMS): δ 14.1, 22.7, 29.3, 29.7, 31.9, 37.1, 48.6, 126.4, 126.5,
128.8, 129.0, 129.2, 129.3, 172.2, 174.8, 202.7; IR (KBr, cm-1): ν 753,
1199, 1229, 1379, 1401, 1459, 1501, 1719, 1746, 2853, 2923, 2956, 3489;
HPLC: Chiralpak AD-H (Hexanes/i-PrOH = 80/20, flow rate = 0.5 mL/min,
λ = 210 nm): major diastereomer: tR = 31.6 min (minor), 47.0 min (major); mi-
nor diastereomer: tR = 38.6 min (major), 45.1 min (minor).
General Procedure for Large-Scale Michael Addition
Isobutyraldehyde (4a, 0.2 mol) was added to a mixture of catalyst
3 (1 mol%) and corresponding maleimide 5 (0.1 mol) in toluene
(250 mL). The reaction mixture was stirred at ambient temperature
for 12 h. After maleimide was consumed by TLC analysis, the solvent
was removed under reduced pressure and the crude product was puri-
fied using column chromatography eluting with ethyl acetate/petroleum
ether. The ee of the products was determined by chiral HPLC analysis
using Chiral columns.
TABLE 1. Solvent optimizationa
TABLE 2. Screening of the catalyst loadinga
Entry
Solvent
CHCl3
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
82
81
95
97
45
74
80
68
87
82
91
95
12
42
84
51
Entry
X (mol%)
Time (h)
Yieldb (%)
eec (%)
THF
1,2-Dichloroethane
Toluene
CH3OH
H2O
Ethyl acetate
Acetonitrile
1
2
3
4
5
15
10
5
1
0.5
1
2
3
10
48
98
97
96
95
83
92
95
97
99
99
aExperimental conditions (unless stated otherwise): Isobutyraldehyde (4a,
0.40 mmol), N-phenylmaleimide (5a, 0.20 mmol), and 10 mol% catalyst 3a in
1.0 mL solvent at ambient temperature.
aExperimental conditions (unless stated otherwise): Isobutyraldehyde (4a,
0.40 mmol), N-phenylmaleimide (5a, 0.20 mmol), X mol% catalyst 3a in 1.0 mL
toluene at ambient temperature.
bIsolated yield.
bIsolated yield.
cDetermined by chiral HPLC analysis.
cDetermined by chiral HPLC analysis.
Scheme 1. Synthetic routes of thioureas 3.
Chirality DOI 10.1002/chir

THIOUREA CATALYZED ENANTIOSELECTIVE MICHAEL ADDITION
125
TABLE 3. Substrate studiesa
to 0.5 mol%, the yield was slightly lower, but the reaction
time was prolonged to 48 h. Thus, the optimized catalyst
loading was chosen as 1 mol% (Table 2, entry 5).
To investigate the scope of this reaction, a wide range of
maleimides bearing different N-substituents was subjected
to the new diterpene-derived bifunctional thiourea-catalyzed
Michael reaction under the optimized conditions. The results
are collected in Table 3. As shown in Table 3, the reaction has
a broad substrate scope with respect to the maleimides. The
yield varied as the substituent on the N-phenly moiety of
the maleimides, but the enantioselectivity was to some
degree independent of the substituent. All the maleimides
gave the desired Michael adducts in good to high yields
(62–96%) and excellent enantioselectivities (92–99%) regard-
less of the electronic and sterical properties of the substituents
(Table 3, entries 1–11). For the N-alkyl substituted maleimide
5l, the conjugate addition also produced excellent both in
terms of yield and enantioselectivity (Table 3, entry 12). In
the case of maleimide 5m, only a trace amount of the product
was obtained; both thiourea 3a and 3b were inefficient
(Table 3, entry 13). This is probably due to the influence of
the H-bonding interaction by the active N-H of maleimide 5m.
To further demonstrate the scope of this organocatalytic
Michael reaction, cyclohexanecarboxaldehyde 4b was also
evaluated for the reaction with various maleimides (Table 4,
entries 1–5). These reactions proceeded smoothly and the
corresponding Michael adducts were obtained with high
yields (79–90%) and enantioselectivities (92–99%). When
n-hexalaldehyde 4c was used as a donor, two stereogenic
carbon centers were formed in this reaction with good
yield and ee values (Table 4, entries 6, 7).
Entry
R
Cat
Product Yieldb (%) eec (%)
1
2
3
4
5
6
7
C6H5(5a)
4-F-C6H4(5b)
3-Cl-C6H4(5c)
4-Cl-C6H4(5d)
3-Br-C6H4(5e)
4-Br-C6H4(5f)
3-NO2-C6H4
(5g)
4-NO2-C6H4
(5h)
4-CH3-C6H4
(5i)
3a/3b
3a/3b
3a/3b
6a/6a’
6b/6b’
6c/6c’
95/96
93/95
85/86
70/75
70/72
86/84
62/62
99/99
94/98
98/97
97/98
99/98
97/99
98/94
3a/3b 6d/6d’
3a/3b
3a/3b
3a/3b
6e/6e’
6f/6f’
6g/6g’
8
3a/3b
3a/3b
3a/3b
3a/3b
6h/6h
6i/6i’
6j/6j’
70/71
95/96
78/58
93/92
92/98
99/99
97/93
99/99
9
10
11
2,6-(CH3)2-
C6H3(5j)
2-CH3O-C6H4
(6k)
6k/6k’
12
13
Bn(5l)
3a/3b
3a/3b
6l/6l’
-/-
94/95
trace/
trace
91/98
-/-
d
H(5m)
We further performed large-scale asymmetric Michael
reactions with 100 mmol of N-phenylmaleimide 5a and 2
equiv. of isobutyraldehyde 4a (Scheme 2). The same catalyst
loading of 1 mol% as in the experimental scale was used. Using
the same procedure, both the yield and enantioselectivity were
maintained at the same level for large-scale reactions, which of-
fers a great possibility for application in industry.
aExperimental conditions (unless stated otherwise): Aldehyde (4a, 0.40 mmol),
maleimide (5, 0.20 mmol), 1mol% catalyst 3a in 1.0 mL toluene at ambient
temperature for 10–72 h.
bIsolated yield.
cDetermined by chiral HPLC analysis.
dNot determined.
TABLE 4. Substrate studiesa
Entry
R1
R2
R
Cat
Product
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
-CH2(CH2)3CH2- (4b)
-CH2(CH2)3CH2- (4b)
-CH2(CH2)3CH2- (4b)
-CH2(CH2)3CH2- (4b)
-CH2(CH2)3CH2- (4b)
C6H5(5a)
3a/3b
3a/3b
3a/3b
3a/3b
3a/3b
3a
7a/7a’
7b/7b’
7i/7i’
7k/7k’
7l/7l’
8a
85/90
87/86
79/87
79/83
87/79
84
—
—
95/99
92/99
98/99
98/99
99/95
85/60
90/99
4-F-C6H4(5b)
4-CH3-C6H4(5i)
2-CH3O-C6H4(5k)
Bn(5l)
—
—
—
H
H
n-C4H10(4c)
n-C4H10(4c)
C6H5(5a)
C6H5(5a)
2.2/1
2.7/1
3b
8a’
75
aExperimental conditions (unless stated otherwise): Aldehyde (4b-4c, 0.40 mmol), maleimide (5, 0.20 mmol) and 1mol% catalyst 3 in 1.0 mL toluene at ambient
temperature for 6–36 h.
bIsolated yield.
cDetermined by 1H NMR analysis.
dDetermined by chiral HPLC analysis.
Chirality DOI 10.1002/chir

126
SONG ET AL.
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Contract grant sponsor: National Natural Science Foundation
of China; Contract grant numbers: 20772113. Contract grant
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Chirality DOI 10.1002/chir