Homochiral bifunctional L-prolinamide- and L-bis-prolinamide-catalyzed asymmetric aldol reactions performed in wet solvent-free conditions

Article abstract of DOI:10.1002/chir.23283

In this study, the novel bifunctional homochiral thiourea-L-prolinamides 1–4, tertiary amino-L-prolinamide 5, and bis-L-prolinamides 6 and 7 were prepared from enantiomerically pure (11R,12R)-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene 8 and (11S,12S

Full text of DOI:10.1002/chir.23283

Received: 22 June 2020
DOI: 10.1002/chir.23283
Revised: 25 September 2020
Accepted: 5 October 2020
R E G U L A R A R T I C L E
Homochiral bifunctional L-prolinamide- and
L-bis-prolinamide-catalyzed asymmetric aldol
reactions performed in wet solvent-free conditions
1
2
3
Gabriela Huelgas | Ratnasamy Somanathan
| Julio M. Hernández Pérez
|
1
1
Haydee Rojas Cabrera | Maximiliano de la Higuera Macías
|
1
1
1
Alejandra Domínguez-Huerta | Rocío Sabala | Cecilia Anaya de Parrodi
1
Departamento de Ciencias Químico
Abstract
Biológicas, Universidad de las Americas
Puebla, Cholula, Puebla, Mexico
In this study, the novel bifunctional homochiral thiourea-L-prolinamides 1–4,
tertiary amino-L-prolinamide 5, and bis-L-prolinamides 6 and 7 were prepared
2
Centro de Graduados e Investigación en
Química, Tecnológico Nacional de
México/Instituto Tecnológico de Tijuana,
Tijuana, Baja California, Mexico
from
enantiomerically
pure
and
(11R,12R)-11,12-diamino-9,10-dihydro-
(11S,12S)-11,12-diamino-9,10-dihydro-
9,10-ethanoanthracene
8
3
Facultad de Ciencias Químicas,
9,10-ethanoanthracene ent-8. Highly enantioselective and diastereoselective
aldolic intermolecular reactions (up to 95% enantiomeric excess, 93:7 anti/syn)
between aliphatic ketones (20 equiv) and a range of aromatic aldehydes
(1 equiv) were successfully carried out in the presence of water (10 equiv) and
monochloroacetic acid (10 mol%), solvent-free conditions, at room tempera-
ture over 24 h using organocatalysts 1–7 (5 mol%). Stereoselective induction
using density functional theory–based methods was consistent with the
experimental data.
Benemérita Universidad Autónoma de
Puebla, Puebla, Mexico
Correspondence
Cecilia Anaya de Parrodi, Universidad de
las Américas Puebla, Departamento de
Ciencias Químico Biológicas, Santa
Catarina Mártir, 72820, Cholula, Puebla,
México.
Email: cecilia.anaya@udlap.mx
K E Y W O R D S
Funding information
Consejo Nacional de Ciencia y Tecnología
1,2-diamines, aldol reaction, asymmetric organocatalysis, bifunctional prolinamides, C
symmetry axis, stereoselectivity, wet solvent-free
2
-
(
CONACYT), Grant/Award Numbers:
90754, 170296, 286620
2
1
| INTRODUCTION
Asymmetric C–C bond formation reactions are impor-
tant in organic synthesis. In particular, there are several
reports of the asymmetric aldol reaction between ketones
and aldehydes. This reaction produces β-hydroxy-carbonyl
compounds with one or more stereogenic centers. These
compounds have wide applications as building blocks of
Asymmetric organocatalysis has had a tremendous
impact on synthetic organic chemistry since 2000. It is
an environmentally benign process that requires no
metallic species.
usage of organocatalysts under solvent-free or very con-
centrated catalytic reaction conditions. The successful
use of organocatalysts with water as a solvent or in wet
solvent-free conditions has also been reported. Water
1,2,4,5,14
Several examples exist in the
11–13
complex biologically active molecules.
List and
6
Barbas reported the aldolic reaction involving an aldehyde
and a ketone, catalyzed by chiral proline in DMSO. They
7
reported that proline behaves as
a
bifunctional
might play an important role in the transition state of
the asymmetric organocatalyzed reactions, through the
formation of hydrogen bonds and other noncovalent
organocatalyst, where the proton donor group activates
the electrophile, and the amine group activates the
nucleophile, through the formation of an enamine. Thus,
8
–10
14–21
interactions.
proline mimicks the natural enzyme aldolase.
Chirality. 2020;1–15.
wileyonlinelibrary.com/journal/chir
© 2020 Wiley Periodicals LLC.
1

2
HUELGAS ET AL.
Since this pioneering work for the aldol reaction,
there are other reports of the use of enantiopure bifunc-
2 | EXPERIMENTAL
tional L-prolinamide as organocatalysts, such as A, B, C,
2.1 | Materials and instruments
and
D
(Figure 1), with moderate to good
stereoselectivities and yields. In particular, these
All reagents were purchased from commercial suppliers
and used without further purification. THF was freshly
distilled from a sodium-benzophenone ketyl radical
under an argon atmosphere. NMR spectra were
recorded on a Bruker 400 MHz spectrometer. The
prolinamides contain the trans-1,2-diaminocyclohexane
22–25
moiety as backbone.
Herein, we synthesized novel homochiral bifunc-
tional L-prolinamide organocatalysts 1–6 from enan
tiopure (11R,12R)-11,12-diamino-9,10-dihydro-9,10-eth-
1
chemical shifts of the peaks in the H NMR spectra
23,26,27
anothracene 8
L-prolinamide organocatalyst
11S,12S)-11,12-diamino-9,10-dihydro-9,10-ethanothrace
(Figure 2). We also prepared
were referenced to the resonance of tetramethylsilane.
13
7
from enantiopure
The chemical shifts of the peaks in the C NMR spec-
tra were referenced to the resonance of the residual
solvent. Infrared spectra were recorded on a Bruker
Tensor 27 spectrometer. The ee values were measured
by doing chiral high-performance liquid chromatogra-
phy (HPLC) purification at room temperature using an
Agilent Infinity with an ultraviolet-visible (UV-vis)
detector, with Chiralpak AD-H and Chiralcel OD-H
columns.
(
ne ent-8 (Scheme 4). We evaluated the novel organocat-
alysts in the asymmetric aldol reaction in wet
solvent-free conditions, and in the presence of
chloroacetic acid as additive. Theoretical calculations of
the transition state of acetone and p-nitrobenzaldehyde
with organocatalyst
outcome.
6 supported the experimental
FIGURE 1 Examples of recently
synthesized L-prolinamide bifunctional
organocatalysts used in asymmetric aldol
reactions
FIGURE 2 Structures of the homochiral
bifunctional L-prolinamides and L-bis-prolinamides
1
–6

HUELGAS ET AL.
3
2
2
.2 | Synthesis
(11R,12R)-11-[Di(phenyl)methylenethiourea]-12-amino-
9
,10-dihydro-9,10-ethanoanthracene (11)
ꢀ
20
.2.1 | General procedure for the
White solid (72% yield), m.p. 145–147 C. [α]
(c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 105 C, δ):
= +60.5
D
1
ꢀ
synthesis of thiourea-L-prolinamides 9–12
3
6
2
.78–2.95 (m, 6H), 3.91 (b, 1H), 4.15 (d, J = 2.4 Hz, 1H),
(11R,12R)-11,12-Diamino-9,10-dihydro-
4.51 (d, J = 2.2 Hz, 1H), 6.75 (s, 1H), 6.84 (d, J = 6.8 Hz,
1H), 7.11–7.35 (m, 16H). C NMR (50 MHz, DMSO-d6,
105 C, δ): 48.0, 51.8, 59.1, 60.4, 62.6, 122.4, 122.5, 124.2,
13
9
1
,10-ethanoanthracene 8 (350 mg, 1.48 mmol) and
.49 mmol of crude (S)-1-phenylethyl isothiocyanate,
ꢀ
(
3,5-trifluoromethyl)phenyl isothiocyanate, di(phenyl)
124.5, 124.6, 124.7, 125.4, 125.8, 125.9, 126.8, 137.7, 138.4,
139.8, 140.8, 141.0, 141.3, 180.8.IR (KBr) υmax 3415, 3356,
3237, 3028, 2928, 2854, 2117, 1728, 1678, 1580, 1528,
methylene isothiocyanate, or benzylisothiocyanate were
dissolved in dichloromethane (10 ml) under a nitrogen
atmosphere at 0 C. Triethylamine (0.22 ml, 165 mg) was
ꢀ
−1
1472, 1402, 1350, 1255, 1225, 1118, 1074, 1027 cm .
added to the reaction mixture, which was then stirred at
HRMS (FAB+) m/z calcd. for [C H N S ]: 462.2004,
found 462.2014.
30
28 3 1
ꢀ
0
ꢁ
C until the disappearance of the isothiocyanates for
2 h. The reaction was then quenched by adding water,
and the organic phase was first extracted with CH Cl
(11R,12R)-11-(benzylthiourea)-12-amino-9,10-dihydro-
2
2
(
3 × 20 ml), followed by drying over anhydrous sodium
9,10-ethanoanthracene (12)
ꢀ
20
sulfate. The solvent was removed at a reduced pressure.
Crude amino-thioureas 9–12 were isolated and
purified by flash chromatography on silica gel
White solid (70% yield), m.p. 134–136 C. [α]
= +58.3
D
1
ꢀ
(c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 85 C, δ):
3
6
3.00 (b, 5H), 3.89 (b, 1H), 4.14 (d, J = 2.6 Hz, 1H), 4.48 (d,
(
2
triethylamine/SiO = 2.0% v/w, hexanes/ethyl acetate
:1, v/v).
J = 2.6 Hz, 1H), 4.66 (s, 2H), 6.76 (d, J = 7 Hz, 1H),
2
13
ꢀ
7.10–7.35 (m, 12H). C NMR (50 MHz, DMSO-d , 85 C,
6
δ): 47.0, 48.1, 51.7, 59.0, 62.5, 122.4, 122.5, 124.2, 124.5,
124.6, 124.7, 125.4, 126.0, 126.8, 137.5, 137.7, 138.5, 139.9,
141.3, 181.4. IR (KBr) υmax 3304, 3274, 3115, 3062, 2974,
2946, 2874, 1659, 1531, 1457, 1369, 1345, 1287, 1250,
(
9
11R,12R)-11-[(S)-1-Phenylethylthiourea]-12-amino-
,10-dihydro-9,10-ethanoanthracene (9)
ꢀ
20
White solid (78% yield), m.p. 133–135 C. [α]
= +62.2
ꢀ
D
1
−1
(
c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 115 C, δ):
1162, 1117, 1082, 1028 cm . HRMS (FAB+) m/z calcd.
3
6
1
.44 (d, J = 7 Hz, 3H), 2.80 (b, 4H), 3.89 (b, 1H), 4.15 (d,
for [C H N S ]: 386.1691, found 386.1694.
24
24 3 1
J = 2.4 Hz, 1H), 4.46 (d, J = 2.6 Hz, 1H), 5.49–5.55 (m,
1
3
1
H), 6.55 (b, 1H), 7.12–7.35 (m, 13H). C NMR (50 MHz,
ꢀ
DMSO-d , 115 C, δ): 21.5, 48.0, 51.8, 52.3, 59.1, 62.4,
2.2.2 | General procedure for the
synthesis of thiourea-L-prolinamides 13–16
6
1
1
3
1
22.3, 122.4, 124.2, 124.4, 124.7, 125.1, 126.7, 137.6, 138.3,
39.8, 141.2, 142.5, 180.2. IR (KBr) υmax 3414, 3361, 3232,
026, 2928, 2869, 1580, 1529, 1472, 1405, 1377, 1350,
A
solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-
−
1
305, 1230, 1147, 1114, 1082, 1023, 1003 cm . HRMS
2-carboxylic acid (600 mg, 2.76 mmol) and triethylamine
(279 mg, 0.384 ml, 2.75 mmol) was prepared in anhy-
drous THF (50 ml). This solution was then cooled down
(FAB+) m/z calcd. for [C H N S ]: 400.1847, found
25 26 3 1
4
00.1855.
ꢀ
to 0 C. Ethyl chloroformate (300 mg, 0.264 ml,
(
1
11R,12R)-11-[(3,5-Trifluoromethyl)phenylthiourea]-
2-amino-9,10-dihydro-9,10-ethanoanthracene (10)
2.76 mmol) was then added dropwise, and the resulting
solution was stirred for 30 min. A solution of thiourea
(2.76 mmol) in anhydrous THF (25 ml) was added to the
solution described above, and the solution thus obtained
ꢀ
White
solid
(89%
yield),
m.p.
125–127 C.
20
1
[
α]D = +24.0 (c = 1, CHCl ). H NMR (200 MHz,
3
ꢀ
CDCl , δ): 1.73 (b, 2H), 3.12 (b, 1H), 3.38 (b, 1H), 4.13
was left stirring for another 4 h at 0 C. The reaction mix-
3
(
d, J = 2.0 Hz, 1H), 4.30 (d, J = 2.2 Hz, 1H), 6.27 (d,
ture was then filtered, leaving the solvent under reduced
pressure. The residue was dissolved in ethyl acetate
(60 ml). The organic phase was subjected to successive
J = 5.2 Hz, 1H), 7.19–7.60 (m, 9H), 8.13 (s, 2H), 11.06
1
3
(b, 1H). C NMR (50 MHz, CDCl , δ): 3, 53.5, 60.2,
3
1
6
1
1
1
3.6, 118.4, 123.2 (q, J
= 273.8 Hz), 123.6, 124.6,
washes with water, saturated aqueous NaHCO , and
CF
3
26.8, 127.4, 127.6, 127.8, 132.1, 136.3, 137.6, 140.4,
brine. The organic phase was collected, dried over anhy-
drous sodium sulfate, and concentrated by evaporation
under reduced pressure. The product contained in
the concentrated solution was purified by column
chromatography on silica gel using hexanes/ethyl acetate
41.5, 141.7, 180.8. IR (KBr) υmax 3409, 3360, 2926,
−1
605, 1513, 1471, 1379, 1275, 1172, 1126, 1012 cm .
HRMS (FAB+) m/z calcd. for [C H F N S ]:
5
25
20 6 3 1
08.12857, found 508.12821.

4
HUELGAS ET AL.
(2:1, v/v) as an eluent to produce the desired protected
141.5, 141.9, 142.1, 156.1, 171.8, 182.3. IR (KBr) υmax
prolinamide thioureas 13–16.
3301, 3274, 3115, 3061, 2973, 2946, 2874, 1660, 1530,
1
456, 1368, 1345, 1288, 1248, 1161, 1116, 1052,
−
1
(11R,12R)-11-[(S)-1-Phenylethylthiourea]-12-[(S)-
1028 cm . HRMS (FAB+) m/z calcd. for
1
9
-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido]-
,10-dihydro-9,10-ethanoanthracene (13)
[C H N O S ]: 659.3056, found 659.3064.
40
43 4 3 1
ꢀ
20
White solid (78% yield), m.p. 138–140 C. [α]
= −36.9
(11R,12R)-11-(Benzylthiourea)-12-[(S)-1-(tert-
butoxycarbonyl)pyrrolidine-2-carboxamido]-
9,10-dihydro-9,10-ethanoanthracene (16)
D
1
ꢀ
(
c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 85 C, δ):
3
6
1
3
1
.21 (s, 9H), 1.41 (d, J = 6.6 Hz, 3H), 1.76–2.00 (m, 4H),
.09 (s, 1H), 3.20–3.35 (m, 2H), 3.71 (dd, J = 4.2, 2.8 Hz,
H), 4.03–4.06 (m, 1H), 4.36–4.45 (m, 2H), 4.69 (d,
ꢀ
20
White solid (70% yield), m.p. 133–135 C. [α]
= −45.8
D
1
ꢀ
(c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 75 C, δ):
3
6
J = 2.4 Hz, 1H), 5.45 (dd, J = 7.8, 7.0 Hz, 1H), 6.93 (d,
1.27 (s, 9H), 1.75–1.97 (m, 4H), 3.11 (s, 1H), 3.31 (dd,
J = 5.4, 6.6 Hz, 2H), 3.73 (b, 1H), 4.07 (d, J = 7.4 Hz, 1H),
4.36–4.45 (m, 2H), 4.66 (b, 1H), 4.72 (d, J = 2.2 Hz, 2H),
J = 7.8 Hz, 1H), 7.09–7.46 (m, 13H), 7.56 (d, J = 8.2 Hz,
13
ꢀ
1
2
1
1
3
1
H). C NMR (50 MHz, DMSO-d , 85 C, δ): 21.7, 22.8,
6
13
7.6, 30.2, 46.0, 48.4, 51.9, 56.2, 58.8, 59.0, 78.0, 123.4,
23.6, 125.2, 125.3, 125.6, 125.6, 125.8, 126.1, 127.6, 139.1,
41.3, 141.6, 143.6, 153.1, 172.0, 181.7. IR (KBr) υmax
301, 3043, 2973, 2875, 1665, 1525, 1456, 1367, 1249,
7.10–7.37 (m, 13H), 7.50–7.55 (m, 2H).
C NMR
ꢀ
(50 MHz, DMSO-d , 75 C, δ): 22.9, 27.7, 30.2, 46.1, 46.7,
6
48.3, 56.0, 58.8, 59.1, 78.0, 123.5, 123.7, 125.2, 125.4,
125.7, 126.3, 126.4, 126.9, 127.6, 127.8, 138.7, 139.2, 141.3,
141.6, 153.2, 172.0, 182.9. IR (KBr) υmax 3321, 3065, 3026,
2972, 2953, 2930, 2879, 1660, 1526, 1457, 1369, 1344,
−
1
160, 1117, 1086, 1025 cm . HRMS (FAB+) m/z calcd.
for [C H N O S ]: 597.2899, found 597.2904.
35
41 4 3 1
−1
1286, 1253, 1161, 1119, 1086, 1054, 1027 cm . HRMS
(11R,12R)-11-[(3,5-Trifluoromethyl)phenylthiourea])-
(FAB+) m/z calcd. for [C H N O S ]: 583.2743, found
34
39 4 3 1
1
2
9
2-[(S)-1-(tert-butoxycarbonyl)pyrrolidine-
-carboxamido]-9,10-dihydro-
583.2751.
,10-ethanoanthracene (14)
ꢀ
20
White solid (72% yield), m.p. 227–230 C. [α]
= −84.3
2.2.3 | General procedure for the
synthesis of thiourea-L-prolinamides 1–4
D
1
ꢀ
(
c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 85 C, δ):
3
6
1
3
1
8
2
1
1
1
2
1
.14 (s, 9H), 1.68–1.79 (m, 3H), 2.04–2.31 (m, 3H),
.06–3.23 (m, 3H), 4.05–4.23 (m, 2H), 4.36 (d, J = 2.2 Hz,
H), 4.67–4.71 (m, 1H), 7.16–7.71 (m, 10H), 8.02 (s, 1H),
TFA (1 ml) was added to a solution of the protected
thiourea-N-Boc-L-prolinamide (1.0 g) in CH Cl (30 ml).
The mixture thus obtained was stirred at room tempera-
ture for 24 h. The reaction was basified with saturated
aqueous NaHCO to pH 12.0, and the reaction mixture
2
2
13
ꢀ
.82 (b, 1H). C NMR (50 MHz, DMSO-d , 85 C, δ): 23.7,
6
4.4, 24.9, 30.4, 47.3, 48.7, 49.6, 57.4, 59.7, 62.1, 68.4, 80.9,
16.3, 120.7, 122.7 (q, J
25.1, 126.2, 126.7, 126.9, 127.3, 128.5, 130.6, 130.8, 136.9,
38.6, 140.2, 158.5, 171.5, 178.8. IR (KBr) υmax 3308, 3027,
971, 2929, 2875, 1669, 1522, 1455, 1367, 1287, 1249,
1
= 259.7 Hz), 123.3, 124.9,
CF
3
was extracted with CH Cl (3 × 20 ml). The organic
2
2
phase was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was purified by
flash chromatography on deactivated silica gel
−
1
160, 1116, 1086, 1023 cm . HRMS (FAB+) m/z calcd.
for [C H N O F S ]: 705.2334, found 705.2334.
(triethylamine/SiO = 2.0% v/w, ethyl acetate 100%) to
35
35
4
3
6 1
2
afford the desired thiourea-L-prolinamides 1–4.
(11R,12R)-11-[Di(phenyl)methylenethiourea]12-[(S)-
1
9
-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido]-
,10-dihydro-9,10-ethanoanthracene (15)
(11R,12R)-11-[(3,5-Trifluoromethyl)phenylthiourea])-
12-[(S)-pyrrolidine-2-carboxamido]-9,10-dihydro-
9,10-ethanoanthracene (1)
ꢀ
20
White solid (68% yield), m.p. 147–149 C. [α]
= −15.11
D
1
ꢀ
ꢀ
20
(
c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 85 C, δ):
White solid (82% yield), m.p. 173–175 C. [α]
= −41.4
3
6
D
1
ꢀ
1
.84 (s, 9H), 2.00–2.35 (m, 4H), 3.61 (ddd, J = 5.8, 2.8,
(c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 55 C, δ):
3
6
2
.8 Hz, 2H), 4.16 (ddd, J = 3.4, 3.2, 1.2 Hz, 1H), 4.48 (dd,
1.25–1.87 (m, 6H), 2.63–2.74 (m, 1H), 3.50 (dd, J = 5.4,
5.0 Hz, 1H), 3.86–3.90 (m, 1H), 4.38 (d, J = 2.4 Hz, 1H),
4.47 (b, 1H), 4.65 (d, J = 2.0, 1H) 7.20–8.14 (m, 11H), 8.29
J = 2.6, 3.0 Hz, 1H), 4.78 (d, J = 2.8 Hz, 1H), 4.91–5.02
(m, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 7.0 Hz, 1H),
13
13
ꢀ
7
.0 (d, J = 7.8 Hz, 1H), 7.54–7.88 (m, 20H). C NMR
(s, 1H), 9.0 (b, 1H). C NMR (50 MHz, DMSO-d , 55 C,
6
ꢀ
(50 MHz, DMSO-d , 85 C, δ): 22.8, 27.5, 30.0, 46.0, 48.1,
δ): 26.5, 31.1, 47.3, 48.8, 56.8, 60.3, 62.1, 68.4, 116.2, 120.4,
6
1
4
1
1
8.3, 56.3, 56.5, 58.8, 59.2, 60.1, 78.0, 123.3, 123.5, 123.9,
25.5, 125.6, 125.9, 126.0, 126.3, 126.4, 126.5, 126.7, 127.5,
27.6, 127.7, 127.8, 128.1, 128.2, 128.7, 139.0, 139.1, 141.4,
120.2, 122.8 (q, J
= 278.7 Hz), 123.2, 124.5, 124.7,
CF
126.1, 126.4, 126.6, 127.2, 128.5, 130.0, 130.6, 137.0, 139.0,
140.6, 174.6, 178.7. IR (KBr) υmax 3281, 3071, 2951, 2871,

HUELGAS ET AL.
5
1
1
721, 1647, 1630, 1600, 1515, 1470, 1383, 1335, 1274,
227, 1172, 1124 cm . HRMS (FAB+) m/z calcd. for
2.2.4 | General procedure for the
synthesis of reaction intermediate 17
−
1
[
C H N O F S ]: 604.1732, found 604.1740.
30 26 4 1 6 1
A suspension of (11R,12R)-9,10-dihydro-9,10-ethanoa
nthracen-11-amine (S)-mandelate salt (1.00 g, 2.60 mmol),
2,2 -bis (bromomethyl)biphenyl (0.88 g, 2.57 mmol), and
(
11R,12R)-11-[(S)-1-Phenylethylthiourea]-12-[(S)-
0
pyrrolidine-2-carboxamido]-9,10-dihydro-
,10-ethanoanthracene (2)
9
K CO (1.07 g, 7.72 mmol) was prepared in acetonitrile
2
3
ꢀ
20
ꢀ
White solid (82% yield), m.p. 145–148 C. [α]
= −6.9
(20 ml). This suspension was then stirred at 85 C for 2 h.
After incubation, the mixture was washed with brine
(10 ml). The aqueous layer was then extracted with
CH Cl (30 × 3 ml), and the organic phase was dried over
D
1
ꢀ
(
c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 95 C, δ):
3
6
1
3
4
7
.24 (d, J = 6.6 Hz, 3H), 1.42–1.72 (m, 6H), 2.80 (b, 2H),
.32 (t, J = 6.0 Hz, 1H), 3.55 (b, 1H), 4.16–4.23 (m, 2H),
.37 (b, 1H), 5.28 (t, J = 6.6 Hz, 1H), 6.62 (d, J = 7.8, 1H)
2
2
Na SO and concentrated.
2
4
13
.02–7.22 (m, 13H), 7.48 (d, J = 7.8, 1H). C NMR
The concentrated solution thus obtained was sub-
jected to silica gel column chromatography purification
using ethyl acetate/hexane (5:1 v/v) as an eluent to afford
product 17.
ꢀ
(50 MHz, DMSO-d , 95 C δ): 21.6, 25.0, 29.8, 46.0, 48.4,
6
4
1
1
2
1
8.6, 52.0, 55.9, 59.8, 60.0, 123.5, 123.6, 125.1, 125.3,
25.5, 125.7, 125.8, 126.1, 127.7, 138.8, 138.9, 141.3, 141.4,
43.5, 173.7, 181.8. IR (KBr) υmax 3343, 3083, 2974, 2942,
877, 1662, 1532, 1451, 1373, 1346, 1287, 1243, 1162,
(11R,12R)-12-(6,7-Dihydro-5H-dibenzo[c,e]azepin)-
9,10-dihydro-9,10-ethanoanthracen-11-amine (17)
−
1
114, 1050, 1003 cm . HRMS (FAB+) m/z calcd. for
ꢀ
20
[
C H N O S ]: 497.2375, found 497.2375.
Yellow solid (71% yield), m.p. 158–160 C. [α]
= +84
30
33
4
1 1
D
1
(11R,12R)-11-[Di(phenyl)methylenethiourea]12-[(S)-
(c = 1, CHCl ); H NMR (CDCl , 400 MHz, δ): 2.45 (t,
3
3
pyrrolidine-2-carboxamido]-9,10-dihydro-9,10-ethanoan
J = 2.7 Hz, 1H), 3.21 (t, J = 2.9 Hz, 1H), 3.24 (d,
thracene (3)
J = 3.2 Hz, 2H), 3.90 (d, J = 12.1 Hz, 2H), 4.06 (d,
ꢀ
White solid (80% yield), m.p. 135–137 C.
J = 2.7 Hz, 1H), 4.27–4.30 (m, 2H), 4.48 (d, J = 2.4 Hz,
20
1
13
[
α]D = −39.2 (c = 1, CHCl ). H NMR (200 MHz,
1H), 7.06–7.23 (m, 16H). C NMR (CDCl , 100 MHz) δ
3
3
ꢀ
DMSO-d , 125 C, δ): 1.27–1.89 (m, 6H), 3.21 (b, 2H),
47.5, 52.9, 55.0, 58.4, 62.8, 71.3, 124.5, 124.7, 125.0, 126.2,
126.3, 126.4, 126.5, 127.5, 127.7, 127.7, 127.8, 128.1, 128.2,
129.7, 129.8,129.8, 129.8, 130.7, 135.0, 138.9, 139.0, 139.6,
140.2, 140.2, 141.0, 141.4, 142.0, 142.2. IR-FT (KBr)
6
3
6
.57–3.83 (m, 3H), 4.28–4.70 (m, 2H), 5.57 (b, 1H),
13
.83–7.39 (m, 18H), 8.22 (b, 1H), 8.43 (b, 1H). C NMR
ꢀ
(50 MHz, DMSO-d , 125 C, δ): 24.8, 29.6, 45.9, 48.4, 52.3,
6
−
1
5
1
1
5.8, 56.2, 59.8, 60.3, 123.2, 124.9, 125.1, 125.5, 125.6,
25.6, 126.1, 126.5, 127.2, 127.3, 127.6, 127.7, 127.8, 134.8,
36.9, 139.2, 139.7, 141.6, 150.0, 165.7, 173.4. IR (KBr)
νmax/cm : 3275, 3061, 3019, 2960, 2927, 2869, 2809,
1734, 1450, 1368, 1295, 1192, 1168, 1044, 1192, 1168,
1113, 1021. HRMS-FAB+: m/z [M + H] + calcd. for
[C H N ]: 415.2174, found: 415.2175.
Vmax 3300, 3058, 3026, 2945, 2865, 1647, 1614, 1514, 1455,
30
27 2
−
1
1
338, 1288, 1226, 1110, 1077, 1028 cm . HRMS (FAB+)
m/z calcd. for [C H N O S ]: 559.2532, found 559.2527.
35
35 4 1 1
2
.2.5 | General procedure for the
(
2
11R,12R)-11-(Benzylthiourea)-12-[(S)-pyrrolidine-
synthesis of tertiary amino-
prolineamide 18
-carboxamido]-9,10-dihydro-9,10-ethanoanthracene (4)
ꢀ
20
White solid (75% yield), m.p. 147–149 C. [α]
= −31.2
D
1
ꢀ
(
c = 1, CHCl ). H NMR (200 MHz, DMSO-d , 55 C, δ):
Ethyl chloroformate (0.30 g, 2.76 mmol) was added
dropwise to a solution of compound 17 (0.59 g,
2.76 mmol) and triethylamine (0.28 g, 2.76 mmol) in dry
CH Cl (40 ml) over 15 min under argon at 0 C. The
resulting solution was stirred at 0 C for 15 min. A solu-
tion of amine (0.95 g, 2.29 mmol) in dry CH Cl (10 ml)
was then added dropwise. The solution was allowed to
warm up to room temperature and then stirred for an
additional 5 h. The solution was then washed with satu-
rated aqueous NaHCO , dried over anhydrous Na SO ,
and concentrated. The residue was purified by flash chro-
matography using hexane/ethyl acetate (1:1, v/v) as an
eluent, to afford the N-Boc-protected prolinamide 5.
3
6
1
.32 (b, 2H), 1.45–1.92 (m, 4H), 2.59–2.76 (m, 2H), 3.11
(
4
b, 1H), 3.51 (dd, J = 5.2, 5.4 Hz, 1H), 3.73–3.80 (m, 1H),
ꢀ
.34 (d, J = 2.6 Hz, 1H), 4.38–4.46 (m, 1H), 4.59 (d,
2
2
ꢀ
J = 2.6 Hz, 1H), 4.66 (d, J = 5.4 Hz, 1H), 7.08–7.42 (m,
1
3H), 7.58 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 5.6 Hz, 1H).
2
2
1
3
ꢀ
C NMR (50 MHz, DMSO-d , 55 C δ): 25.4, 30.1, 46.3,
6
4
1
1
1
1
7.0, 48.5, 48.7, 55.7, 59.8, 60.2, 123.7, 123.8, 125.4, 125.5,
25.9, 126.0, 126.6, 127.0, 127.5, 128.0, 138.7, 139.1, 141.4,
41.5, 173.9, 182.8. IR (KBr) υmax 3291, 3069, 2954, 2869,
651, 1513, 1459, 1342, 1316, 1286, 1227, 1158, 1105,
3
2
4
−
1
056 cm . HRMS (FAB+) m/z calcd. for
[
C H N O S ]: 483.2219, found 483.2219.
29 31 4 1 1

6
HUELGAS ET AL.
(
2
9
11R,12R)-[(S)-tert-Butoxycarbonyl-pyrrolidine-
-carboxamido]12-(5H-dibenzo[c,e]azepin)-
2.2.7 | General procedure for the
synthesis of N-Boc-protected L-bis-
prolinamides 19 and 20
,10-dihydro-9,10-ethanoanthracene (18)
ꢀ
20
White solid (78% yield), m.p. 125–127 C. [α]
= −19.6
D
1
ꢀ
(
c = 1, CHCl3 H NMR (400 MHz, DMSO-d , 90 C δ):
Ethyl chloroformate (0.72 g, 6.6 mmol) was added
6
1
4
1
3
1
1
1
1
2
1
.00 (s, 9H), 1.74–2.00 (m, 7H), 2.60 (b, 2H), 3.85–4.39 (m,
dropwise to a solution of N-Boc-L-proline (1.42 g,
H), 4.86–5.08 (m, 2H), 7.14–7.59 (m, 16H), 7.72–7.77 (m,
6.6 mmol) and triethylamine (0.67 g, 6.6 mmol) in dry
13
ꢀ
ꢀ
H). C NMR (100 MHz, DMSO-d , 90 C δ): 24.0, 33.9,
CH Cl2 (40 ml) over 15 min under argon at 0 C.
6
2
ꢀ
4.8, 37.9, 41.0, 56.0, 58.4, 59.0, 62.0, 65.9, 68.7, 88.0,
34.1, 134.6, 135.2, 135.4, 135.7, 136.1, 136.3, 136.9, 137.1,
37.2, 137.3, 137.6, 138.1, 138.9, 139.8, 140.1, 140.4, 144.0,
44.3, 149.7, 150.2, 150.3, 150.6, 151.0, 151.1, 151.6, 151.7,
The resulting solution was stirred at 0 C for 15 min.
Then,
a
solution
of
(11R,12R)-11,12-diamino-
(11R,12R)-8 or
9,10-dihydro-9,10-ethanoanthracene
(11S,12S)-11,12-diamino-9,10-dihydro-9,10-ethanoanthra
cene (11S,12S)-8 in dry CH Cl (10 ml) was added to it
−1
51.8, 163.9, 181.7. IR-FT (KBr) νmax/cm : 3648, 3319,
950, 2925, 2871, 2799, 1675, 1507, 1477, 1456, 1388,
363, 1312, 1246, 1226, 1158, 1116, 1086, 1025. HRMS-
2
2
dropwise. The resulting solution was allowed to warm up
to room temperature and then stirred for a further 5 h.
The mixture was washed with saturated aqueous
NaHCO3, dried over anhydrous Na SO , and
FAB+: m/z [M + H] + calcd. for [C H O N ]: 612.3226,
found: 612.3218.
40
42 3 3
2
4
concentrated. The residue was purified by flash chroma-
tography using ethyl acetate/methanol (1: 1, v/v) as
an eluent to afford the desired N-Boc-protected
bis-prolinamides 19 or 20.
2
.2.6 | General procedure for the
synthesis of tertiary amino-prolineamide 5
A solution of N-Boc-protected prolinamide 18 (0.6 g,
(11R,12R)-11,12-Bis[(S)-1-tert-Butoxycarbonyl-
pyrrolidine-2-carboxamido]-9,10-dihydro-
9,10-ethanoanthracene (19)
0
.98 mmol) and TFA (0.34 g, 0.23 ml, 2.94 mmol) was
prepared in CH Cl (5 ml). This solution was then stirred
2
2
ꢀ
20
ꢀ
at room temperature for 24 h. An aqueous solution of
White solid (82% yield), m.p. 94–96 C. [α]
= −96.5
6
D
1
ꢀ
NaHCO was then utilized to adjust the solution's pH to
(c = 1.5, CHCl ); H NMR (400 MHz, DMSO-d , 90 C
3
3
1
2. The mixture was diluted with CH Cl , and the phases
δ): 1.29 (s, 18H), 1.73–1.96 (m, 8H), 3.27–3.37 (m, 4H),
3.87 (b, 2H), 4.05 (t, J = 4.0 Hz, 2H), 4.44 (b, 2H),
2
2
were separated. The aqueous layer was extracted with
dichloromethane (2 × 100 ml), and the combined
organics were washed with a small volume of brine. The
organic phase was then dried over anhydrous sodium sul-
fate and concentrated. The crude product was purified by
column chromatography on silica gel using methanol/
ethyl acetate (1:9, v/v) as an eluent, to give the desired
product 5.
13
7.10–7.27 (m, 8H), 7.35–7.36 (m, 2H).
C NMR
ꢀ
(100 MHz, DMSO-d , 90 C δ): 21.7, 27.9, 30.6, 46.2,
6
47.9, 54.7, 58.9, 78.1, 123.9, 125.3, 125.7, 125.7, 139.7,
−
1
141.2, 153.3, 171.9. IR (KBr) νmax/cm : 3287, 3044,
2960, 2928, 2886, 1739, 1681, 1653, 1536, 1453, 1416,
1392, 1368, 1329, 1284, 1234,1202, 1159, 1086. HRMS
+
(FAB ) m/z calcd. for [C H N O ]: 631.3496, found
36
47 4 6
631.3503.
(11R,12R)-12-(6,7-Dihydro-5H-dibenzo[c,e]azepin)-
9
2
,10-dihydro-9,10-ethanoanthracen-pyrrolidine-
(11S,12S)-11,12-Bis[(S)-1-tert-Butoxycarbonyl-
pyrrolidine-2-carboxamido]-9,10-dihydro-
9,10-ethanoanthracene (20)
-carboxamide (5)
ꢀ
20
D
Yellow solid (80% yield), m.p. 223–225 C. [α]
= −20.1
1
ꢀ
20
ꢀ
(
c = 0.87, CHCl ), H NMR (CDCl , 400 MHz, δ): 1.25 (b,
White solid (78% yield), m.p. 115–117 C, ½αꢂ = − 10.7
3
3
D
1
ꢀ
2
1
H), 1.77 (t, J = 6.6 Hz, 2H), 2.16–2.21 (m, 2H), 2.72 (b,
H), 3.0–3.04 (m, 1H), 3.33 (d, J = 12.3 Hz, 2H), 3.66 (d,
(c = 1.0, CHCl ); H NMR (400 MHz, DMSO-d , 90 C): δ
3
6
1.40 (s, 18H), 1.72–1.80 (m, 6H), 1.96–2.01 (m, 2H),
3.23–3.28 (m, 3H), 3.87 (d, J = 5.4 Hz, 2H), 4.0–4.05 (m,
2H) 4.31 (b, 2H), 7.13–7.26 (m, 7H), 7.34–7.36 (m, 4H).
J = 12.4 Hz, 3H), 3.98 (t, J = 6.2, 1H), 4.36 (d, J = 8.4 Hz,
13
1
H), 4.44 (b, 1H), 4.63 (b, 1H), 7.10–7.50 (m, 16H).
C
13
ꢀ
NMR (CDCl , 100 MHz, δ): 25.9, 30.8, 47.1, 47.5, 49.5,
C NMR (100 MHz, DMSO-d , 90 C): δ 22.8, 27.8, 30.5,
3
6
5
1
1
3
2.9, 55.0, 60.3, 70.1, 124.8, 125.0, 125.2, 125.6, 126.6,
26.6, 126.8, 127.7, 127.8, 128.4, 130.3, 134.5, 140.0, 140.8,
40.9, 141.3, 141.8, 172.0. IR-FT (KBr) νmax/cm : 3372,
46.1, 48.7, 55.2, 59.3, 78.2, 123.6, 123.7, 125.4, 125.6,
−
1
125.7, 139.0, 141.7, 153.2, 171.9. IR (KBr) νmax/cm :
3415, 3329, 3310, 3293, 2970, 2929, 2872, 1669, 1653,
1507, 1477, 1457, 1363, 1285, 1245, 1227, 1158, 1116,
−
1
318, 2966, 1602, 1406, 1251, 1197, 1117, 1075, 1043, 937.
+
HRMS-FAB+: m/z [M + H] + calcd. for [C H O N ]:
1087, 1026. HRMS (FAB ) m/z calcd. for [C H N O ]:
35
34
1
3
36 47 4 6
5
12.2702, found: 512.2714.
631.3496, found 631.3503.

HUELGAS ET AL.
7
2
.2.8 | General procedure for the
the desired aldehyde (1.0 equiv) were added in
succession. The reaction mixture was then stirred at
room temperature and monitored by thin-layer
chromatography. Upon completion, 3 ml of a saturated
synthesis of L-bis-prolinamides 6 and 7
TFA (2 ml) was added to a solution of the protected bis-
prolinamides (1.0 g) in CH Cl (30 ml). The resulting
solution of NH Cl was added. The reaction mixture was
2
2
4
mixture was stirred for 48 h. The reaction mixture was
then extracted with CH Cl (3 × 5 ml). The organic phase
2
2
then rendered basic with saturated aqueous NaHCO at
was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The product was
obtained by purification of the concentrated solution by
flash chromatography on silica gel using hexane/ethyl
acetate (2:1, v/v) as an eluent, to afford the desired
product. The ee values were determined by chiral HPLC
analysis, and the configuration was assigned as R by
comparing the experimental retention time to literature
3
pH 12.0 and extracted with CH Cl (3 × 20 ml). The
2
2
organic phase was dried over anhydrous sodium sulfate
and concentrated. The residue was purified by flash
chromatography on deactivated silica gel (triethylamine/
SiO = 2.0% v/w, ethyl acetate 100%), to afford the desired
2
bis-prolinamides 6 and 7.
28
(11R,12R)-11,12-Bis[(S)-prolyl]-9,10-dihydro-
values.
9
,10-ethanoanthracene-1,2-diamine (6)
ꢀ
20
ꢀ
White solid (75% yield), m.p. 107–109 C. [α]
= −94
D
1
(
(
(
(
4
7
3
1
1
1
1
4
c = 1.5, CHCl ; H NMR (400 MHz, CDCl , δ): 1.18–1.21
3 | RESULTS AND DISCUSSION
3.1 | Synthesis of catalysts
3
3
m, 3H), 1.57–1.63 (m, 2H), 1.77–1.85 (m, 1H), 2.0–2.15
m, 3H), 2.67–2.73 (m, 1H), 2.82–2.88 (m, 1H), 3.64–3.69
m, 2H), 3.84–3.86 (m, 1H) 4.06 (dd, J = 7, 7 Hz, 2H),
.30–4.31 (m, 1H), 4.37 (b, 1H), 4.58 (d, J = 8.2 Hz, 1H),
.13–7.40 (m, 11H). C NMR (100 MHz, CDCl , δ): 26.1,
0.9, 47.2, 49.7, 56.7, 60.6, 124.9, 125.0, 125.7, 126.0,
26.7, 126.8, 126.9, 127.0, 138.9, 139.1, 141.0, 141.1, 156.1,
74.9. IR (KBr) νmax 3287, 3044, 2971, 2873, 1656, 1506,
461, 1391, 1367, 1284, 1240, 1161, 1118, 1088,
First, we prepared thiourea-L-prolinamides 1–4, which
contain some potentially useful structural features. These
structural features such as electron-withdrawing groups
and additional chiral centers might influence the stereo-
selectivity of the reaction. Thiourea group also may
contribute to the catalysis of the aldolic reaction, through
13
3
−
1
+
29
045 cm . HRMS (FAB ) m/z calcd. for [C H N O ]:
31.2447, found 431.2447.
the formation of hydrogen bonds. Second, tertiary
26
31 4 2
amino-L-prolinamide 5 has a bulky substituent, which
might favor hydrophobic-hydrophobic interactions.
(11S,12S)-11,12-Bis[(S)-prolyl]-9,10-dihydro-
Finally, bis-L-prolinamide 6 has a C -symmetry axis,
2
9
,10-ethanoanthracene-1,2-diamine (7)
which might have beneficial effects in the stereo-
ꢀ
20
D
ꢀ
30,31
White solid (70% yield), m.p. 175–177 C ½αꢂ = + 220
selectivity of the reaction
(Figure 2).
1
(
(
2
c = 1.0, CHCl ); H NMR (400 MHz, CDCl ), δ 1.63–1.68
We synthesized thiourea-L-prolinamides 1–4 from the
enantiomerically pure diamine (11R,12R)-8 in three steps
(Scheme 1). First, the 1,2-diamine (11R,12R)-8 was made
3
3
m, 2H), 1.90–1.94 (m, 4H), 2.07 (b, 4H), 2.59–2.65 (m,
H), 2.82–2.88 (m, 2H), 3.62 (dd, J = 4.8 Hz, 2H), 3.90 (d,
13
ꢀ
J = 9.8 Hz, 2H), 4.36 (b, 2H), 7.13–7.46 (m, 10H).
NMR (100 MHz, CDCl ), δ 26.2, 31.0, 47.1, 49.5, 56.2,
C
to react in CH Cl at 0 C with (S)-1-phenylethyl isothio-
2
2
cyanate, (3,5-trifluoromethyl)-phenylisothiocyanate, di
(phenyl)methylene isothiocyanate, or benzyl isothiocya-
nate, to afford monoamino-thioureas 9–12 in good yields
(70%–89%). Subsequently, compounds 9–12 reacted with
N-tert-butoxycarbonyl-(S)-proline with ethyl chlorofor-
3
6
0.3, 125.1, 125.6, 126.6, 126.9, 139.3, 140.8, 175.1.
IR (KBr) νmax 3297, 3263, 3045, 3021, 2950, 2942, 2864,
2
1
639, 1645, 1636, 1558, 1540, 1506, 1498, 1457, 1464,
283, 1244, 1167, 1115, 1100, 1061, 1023 cm . HRMS
−
1
+
ꢀ
(FAB ) m/z calcd. for [C H N O ]: 431.2447, found
mate in anhydrous tetrahydrofuran (THF) at 0 C, to
26
31 4 2
4
31.2447.
afford thiourea-N-Boc-prolinamides 13–16, in moderate
yields (68%–78%). Finally, the removal of the Boc group,
with trifluoroacetic acid (TFA) in methylene chloride at
room temperature, afforded the deprotection of com-
pounds 13–16. Thiourea-L-prolinamides 1–4 were
isolated in good yields (75%–82%). The overall yields of
these syntheses were in the range of 36%–57%
(Scheme 1).
2
.2.9 | General procedure for the aldol
reaction of aromatic aldehydes with cyclic
ketones
Monochloroacetic acid (10 mol%) and H O (10 equiv)
2
were added under stirring to a solution of catalyst
We also synthesized the tertiary amino-L-prolinamide
5 (Scheme 2).
6
(5 mol%). After 5 min, cyclohexanone (20 equiv) and

8
HUELGAS ET AL.
SCHEME 1 Synthesis of
the thiourea-L-prolinamides
1
–4. Reagents and conditions:
A) isothiocyanate, CH Cl
C; (B) N-tert-butoxycarbonyl-
(
2
2
,
ꢀ
0
(
S)-proline, triethylamine, THF,
ꢀ
ethyl chloroformate, 0 C, 6 h;
(
2 2
C) TFA, CH Cl , room
temperature, 24 h
The overall process began with the exhaustive ami-
5 (80% yield). The overall yield of organocatalyst
5 was 46%.
0
nation of (11R,12R)-8 with 2,2 -bis (bromomethyl)
biphenyl, in the presence of potassium carbonate in
acetonitrile under reflux for 2 h. This reaction led to
the production of the tertiary amino-amine 17 (73%
yield). Compound 17 was then made to react with N-
In order to understand the influence of a C axis of
2
symmetry on the stereoselectivity of the reaction, we pre-
pared the bis-prolinamide 6 from the enantiopure
diamine (11R,12R)-8. This synthesis was achieved in two
steps. First, (11R,12R)-8 was made to react with N-tert-
butoxycarbonyl-(S)-proline to produce compound 19. The
N-Boc deprotection of compound 19 in the presence of
TFA afforded 6. The overall yield of organocatalyst 6 was
62% (Scheme 3).
tert-butoxycarbonyl-(S)-proline,
with
ethyl
ꢀ
chloroformate in anhydrous THF at 0 C, affording the
tertiary amino-N-Boc-prolinamide 18 (78% yield).
Performing a deprotection reaction of compound 18,
with TFA at room temperature, afforded compound
SCHEME 2 Synthesis of the tertiary amino-L-
0
prolinamide 5. Reagents and conditions: (A) 2,2 -bis
(
(
2 3 3
bromomethyl)biphenyl, K CO , CH CN, reflux, 2 h;
B) N-tert-butoxycarbonyl-(S)-proline, triethylamine,
ꢀ
THF, ethyl chloroformate, 0 C, 6 h; (C) TFA, CH
room temperature, 24 h
2 2
Cl ,
SCHEME 3 Synthesis of bis-
prolinamide 6. Reagents and conditions:
A) N-tert-butoxycarbonyl-(S)-proline,
(
triethylamine, THF, ethyl
ꢀ
chloroformate, 0 C, 6 h; (B) TFA,
2 2
CH Cl , room temperature, 24 h
SCHEME 4 Synthesis of bis-
prolinamide 7. Reagents and conditions:
(
A) N-tert-butoxycarbonyl-(S)-proline,
triethylamine, THF, ethyl
ꢀ
chloroformate, 0 C, 6 h; (B) TFA,
2 2
CH Cl , room temperature, 24 h

HUELGAS ET AL.
9
Finally, we prepare the bis-prolinamide 7, using the
compound 20 in the presence of TFA afforded 7. The
overall yield of organocatalyst 7 was 55% (Scheme 4).
Once all homochiral L-prolinamides 1–7 were synthe-
sized, we proceeded to evaluate their activity as
organocatalysts in the asymmetric aldol reaction. Table 1
enantiomeric diamine (11S,12S)-8, to evaluate the match
or mismatch effect of the chiral centers of the two
diamines. First, we prepared the N-Boc protected bis-
prolinamide 20. Then, the N-Boc deprotection of
TABLE 1 Optimization of the asymmetric aldol reaction between acetone and 4-nitrobenzaldehyde catalyzed by 1–7
a
b
Entry
Catalyst, mol%
1 (5)
2 (5)
3 (5)
4 (5)
5 (5)
6 (5)
1 (5)
2 (5)
3 (5)
4 (5)
5 (5)
6 (5)
1 (5)
2 (5)
3 (5)
4 (5)
5 (5)
6 (5)
1 (5)
2 (5)
3 (5)
4 (5)
5 (5)
6 (5)
7 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
6 (1)
6 (2)
6 (10)
Additive, 10 mol%
None
Solvent, 0.3 ml
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
H
2
O, equiv
Yield, %
54
51
67
65
54
32
60
65
67
61
61
45
55
51
63
42
50
53
90
98
86
97
92
83
79
98
98
96
92
74
31
63
92
ee, %
1
2
3
4
5
6
7
8
9
None
None
None
None
None
None
10
33 (R)
22 (R)
40 (R)
26 (R)
64 (R)
53 (R)
47 (R)
43 (R)
43 (R)
40 (R)
56 (R)
44 (R)
74 (R)
58 (R)
68 (R)
60 (R)
67 (R)
72 (R)
88 (R)
73 (R)
76 (R)
78 (R)
90 (R)
84 (R)
56 (R)
84 (R)
76 (R)
80 (R)
43 (R)
74 (R)
83 (R)
85 (R)
66 (R)
None
None
None
None
None
None
None
10
None
10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
None
10
None
10
None
10
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
None
None
None
None
None
None
10
10
10
10
10
10
10
CH
THF
CH CN
2
Cl
2
10
10
3
10
DMSO
MeOH
None
None
None
10
10
10
10
10
a
Isolated yield after purification by silica gel column chromatography.
b
The ee value was determined by HPLC using a Chiralcel AS-H column and hexane isopropanol as eluent.

10
HUELGAS ET AL.
shows the optimized results in the aldol reaction of ace-
tone (20 equiv) and p-nitrobenzaldehyde (1 equiv) at
room temperature during 24 h, using organocatalysts 1–7
in the presence or absence of water, chloroacetic acid,
and/or solvent. We observed moderate yields (32%–67%)
and enantioselectivities (22%–64%) under solvent free
conditions and in absence of chloroacetic acid (Table 1,
entries 1–6). Interestingly, addition of 10 equivalents of
water to the reaction gave very similar yields (45%–67%),
but enantioselectivities were slightly enhanced (40%–
does not improve the enantiomeric excess of the aldol
reaction.
We hypothesized that introducing two prolinamide
rings on the rigid anthracene framework may provide a
35,36
bifunctional catalyst.
We assumed that one
prolinamide is acting as a proton donor and the other is
forming the enamine in the presence of acid as additive
37–39
(Figure 4).
We also observed that bis-prolinamide 6,
is the match versus bis-prolinamide 7, which is the mis-
match catalyst.
5
6%), compared to solvent free conditions (Table 1,
entries 7–12).
We hypothesized that the addition of an organic acid
might catalyze the enamine formation more
Interestingly, the cyclohexanone compared to acetone
gave better yields (57%–91%), enantioselectivities (78%–
91%), and diastereoselectivities (77:23–93:7 anti/syn) with
no additives (Table 2, entries 1–6). Adding both water
and chloroacetic acid showed increased yields (86%–
32–34
effectively,
so we added chloroacetic acid (10 mol%)
(Table 1, entries 13–18). We observed the best results
97%),
stereoselectivities (85:15–93:7 anti/syn, Table 2, entries
19–24). Organocatalyst give lower yield,
enantioselectivities
(90%–95%),
and
dia-
when chloroacetic acid (10 mol%) and 10 equivalents of
water are added (Table 1, entries 19–24), enhancing
yields (83%–98%) and improving enantioselectivities
7
enantioselectivity and diastereoselectivity than 6 (Table 2,
entry 25). Finally, we also performed the reaction with
organocatayst 6 in the presence of 0.3 ml of toluene, but
neither yield nor enantioselectivity or diastereoselectivity
were improved (Table 2, entry 26).
(73%–90%). We use organocatalyst 7 affording the aldol
product (R) but with lower enantiomeric excess (56%)
compared to bis-prolinamide 6 (84%) (Table 1, entries
2
4 and 25). Then, we performed the reaction in the pres-
ence of organocatalyst 1 with 0.3 ml of some solvents
CH Cl , THF, CH CN, DMSO, MeOH) affording lower
Based on these results, we decided to examine the
scope of the asymmetric aldol reaction of cyclohexanone.
Several substituted aromatic aldehydes (1 equiv) reacted
with cyclohexanone (20 equiv) in the optimized condi-
tions, in the presence of organocatalysts 1, 5, and
6 (Table 3). Best results were obtained with aldehydes
comprising electron-withdrawing groups, such as the
trifluoromethyl, cyano, fluoro, chloro, bromo, and
4-pyridinylcarboxy groups. The asymmetric aldol reaction
afforded moderate-to-high yields (58%–98%), good-to-
high anti/syn diastereoselectivities (73: 27 to 93: 7), and
good-to-high enantioselectivities (77%–94%) (Table 3).
Finally, we do the reaction using benzaldehyde with
organocatalyst 6 (Table 3, entry 25) observing lower yield,
enantio-, and diastereoselectivity compared to other aro-
matic aldehydes with electron withdrawing groups.
(
2
2
3
enantiomeric excess (43%–84%, Table 1, entries 26–30),
compared to the ee with none solvent (88%, Table 1 entry
1
9). We also used organocatalyst 6 in the presence of
water (10 equiv), chloroacetic acid (10 mol%), with cata-
lysts loadings of 1, 2, 5, and 10 mol% (31%–92% yield,
6
5
6–85% ee, Table 1, entries 24, 31–33). We observed that
mol% of catalyst loading gave optimal results (see
Table 1, entry 24).
Based on these results, we strongly suggest that water
molecule may play an important role in the transition
state (Figure 3). The addition of organic acid also
enhances the yield and enantioselectivities of the aldol
reaction. The addition of several solvents to the reaction
FIGURE 3 Plausible transition state involving water
FIGURE 4 Plausible transition state involving acid additive

HUELGAS ET AL.
11
TABLE 2 Optimization of the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde catalyzed by 1–7
a
b
c
Entry
Catalysts
Additive, 10 mol%
None
Solvent, 0.3 ml
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
Toluene
H
2
O, equiv
Yield, %
89
anti/syn
84:16
78:22
79:21
82:18
77:23
93:7
ee, %
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
6
7
6
None
None
None
None
None
None
10
89 (R)
87 (R)
86 (R)
91 (R)
78 (R)
87 (R)
94 (R)
93 (R)
89 (R)
93 (R)
89 (R)
96 (R)
86 (R)
83 (R)
91 (R)
74 (R)
85 (R)
89 (R)
95 (R)
92 (R)
93 (R)
94 (R)
90 (R)
93 (R)
92 (R)
89 (R)
None
87
None
86
None
91
None
80
None
57
None
63
90:10
67:33
88:12
92:8
None
10
71
None
10
73
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
None
10
70
None
10
67
92:8
None
10
56
91:9
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
None
None
None
None
None
None
10
65
88:12
82:18
87:13
85:15
83:17
90:10
88:12
88:12
85:15
87:13
90:10
93:7
52
58
67
72
80
90
10
98
10
94
10
86
10
98
10
97
10
90
88:12
94:6
10
64
a
Isolated yield after purification by silica gel column chromatography.
b
1
The diastereomeric ratio was determined by H NMR spectroscopy and refers to the anti/syn ratio.
c
The ee value was determined by HPLC using a Chiralcel AD-H column and hexane isopropanol as an eluent.
We also decided to examine the scope of the asym-
metric aldol reaction using other carbocyclic and hetero-
cyclic ketones (20 equiv) and p-nitrobenzaldehyde
We calculated the transition state (TS) structure for
the reaction of p-nitrobenzaldehyde and acetone cata-
lyzed by 6. All calculations were performed using the
40
(1 equiv) in the presence of organocatalyst 6 (see Table 4,
Gaussian09 program package, and the relevant chemi-
cal structures were visualize using the Chemcraft 1.6 pro-
entries 1–4). We observed the corresponding anti-aldol
products in moderate-to-good yields (63%–91%),
enantioselectivities (68%–87%), and diastereoselectivities
41
gram. We employed the density functional theory at the
B3LYP/6–31 + G(d,p) level with the CPCM (conductor-
like polarizable continuum model) to describe the solvent
effect; importantly, water was considered as the solvent.
The energies of structure corresponding to energy
(
anti:syn = 65:35–97:3). To assign the stereochemical out-
comes, we compared the products with those reported in
the literature.
28

12
HUELGAS ET AL.
TABLE 3 Performance of organocatalysts 1, 5, and 6 in the asymmetric aldol reaction of cyclohexanone and different aromatic
aldehydes
a
b
c
Entry
Aldehyde
Catalyst
Yield, %
76
anti/syn
92:8
ee%
1
2
3
4
5
6
7
8
9
3-Nitrobenzaldehyde
1
5
6
1
5
6
1
5
6
1
5
6
1
5
6
1
5
6
1
5
6
1
5
6
6
81 (R)
82 (R)
91 (R)
90 (R)
77 (R)
90 (R)
94 (R)
90 (R)
93 (R)
93 (R)
84 (R)
94 (R)
93 (R)
81 (R)
92 (R)
94 (R)
85 (R)
93 (R)
91 (R)
86 (R)
92 (R)
93(R)
96
58:42
96:4
74
2-Nitrobenzaldehyde
4-Trifluoromethylbenzaldehyde
4-Cyanobenzaldehyde
4-Fluorobenzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-(4-Pyridyl)benzaldehyde
Benzaldehyde
87
86:14
85:15
94:6
58
97
97
97:3
97
86:14
95:5
98
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
95
86:14
96:4
85
90
90:10
80:20
77:23
94:6
95
80
98
76
77:23
83:17
93:7
68
75
58
92:8
90
88:12
95:5
75
95
73:27
83:17
84:16
80:20
90
87 (R)
94 (R)
88 (R)
94
80
a
Isolated yield after purification by silica gel column chromatography.
b
1
The diastereomeric ratio was determined by H NMR spectroscopy and refers to the anti/syn ratio.
c
The ee value was determined by HPLC using a Chiralcel AD-H column and hexane isopropanol as an eluent.
minima and transition state structure were validated by
subsequent frequency calculations carried out at the
same level of theory. All minima corresponded to real fre-
quencies, whereas transition states rendered one imagi-
nary frequency each. The transition state structure was
identified through the intrinsic reaction coordinate
method. The Gibbs energy of the transition state was cal-
culated within the standard harmonic-oscillator, rigid-
rotor model.
benzaldehyde is hydrogen bonded to the prolinamide
moiety (O ꢃꢃꢃH distance typical of weak hydrogen bond-
1
1
ing interactions 1.780 Å), whereas the new carbon-
carbon bond begins to be formed (C ꢃꢃꢃC distance of
1
2
1.952 Å). The attack of the enamine occurs on the Re face
of the carbonyl group of p-nitrobenzaldehyde. It is acti-
vated by the NH of the prolinamide moiety, which
involves the diamine (11R,12R)-8-derived compound 6.
The results of these calculations are in agreement with
the observed product stereoselectivities, which confirms
that the reaction outcome depends only on the proline
itself.
The energy of the transition state of the reaction cata-
lyzed by compound 6 corresponded to the formation of
the
R aldol (Figure 5). The carbonyl group of

HUELGAS ET AL.
13
TABLE 4 Scope of the asymmetric aldol reaction between 4-nitrobenzadehyde and different ketones in the presence of organocatalyst 6
a
b
c
Entry
Product
Yield, %
anti/syn
ee, %
1
76
65:35
77 (R)
83 (R)
87 (R)
68 (R)
2
3
4
73
63
91
94:6
97:3
96:4
a
Isolated yield after purification by silica gel column chromatography.
b
1
The diastereomeric ratio was determined by H NMR spectroscopy.
and refers to the anti/syn ratio.
c
The ee value was determined by HPLC using a Chiralcel AD-H column and hexane isopropanol as an eluent.
FIGURE 5 Computed structure of
the proposed transition state TS1 of the
asymmetric aldol reaction involving
4
-nitrobenzaldehyde as a reagent and
compound 6 as catalyst
4
| CONCLUSION
only two steps and in good overall yield. The catalytic
activities of these compounds were evaluated in asym-
metric aldol reactions performed in water (10 equiv) at
room temperature, with catalyst loading of 5 mol%, in
the presence of monochloroacetic acid (10 mol%) over
24 h, and under wet solvent-free conditions. Notably, all
organocatalysts are stable and can be stored for several
months at room temperature without any significant
In this study, the syntheses of novel homochiral bifunc-
tional L-prolinamides 1–5 and L-bis-prolinamides 6 and 7
were reported. Compounds 1–6 were prepared from the
enantiomerically pure diamine (11R,12R)-8. L-bis-
prolinamide 7 was obtained with the enantiomeric
diamine (11S,12S)-8. Organocatalyst 6 was obtained in

14
HUELGAS ET AL.
observable decomposition. In particular, very good results
were obtained with the optimized reaction conditions in
the presence of organocatalyst 6, that is, in the reaction
of cyclohexanone with 4-nitrobenzaldehyde yield of 97%,
diastereoselectivity of anti/syn = 93: 7, and an ee value
of 95%.
2. Owolabi IA, Subba Reddy UV, Chennapuram M, Seki C,
Okuyama Y, Kwon E.
A new type of amino amide
organocatalyzed enantioselective crossed aldol reaction of
ketones with aromatic aldehydes. Tetrahedron. 2018;74:
4705-4711.
3
. Lu L-Q, An X-L, Chen J-R, Xiao W-J. Dual activation in organ-
ocatalysis: Design of tunable and bifunctional organocatalysts
and their applications in enantioselective reactions. Synlett.
2012;2012:490-508.
This result led us to the conclusion that the rigid
backbone of compound (11R,12R)-8, which contains the
4
. Qin Y, Zhu L, Luo S. Organocatalysis in inert C–H bond
functionalization. Chem Rev. 2017;117(13):9433-9520.
. Auvil TJ, Schafer AG, Mattson AE. Design strategies for
enhanced hydrogen-bond donor catalysts. Eur J Org Chem.
trans-1,2-diamino-cyclohexane
moiety,
and
the
stereocenter of L-proline determined the stereochemistry
of the reaction product. The occurrence of hydrogen
bonding interactions due to the addition of 10 equivalents
of water between the aldehyde and L-proline moiety are
observed. Besides, the addition of monochloracetic acid
facilitates the enamine formation. The attack of the
enamine occurs on the Re face of the aldehyde the
carbonyl group as shown in the theoretical calculation of
the transition state. Studies focusing on the use of
organocatalysts 1–7 in other asymmetric reactions
whereby carbon-carbon bonds are formed are currently
underway.
5
2014;2014:2633-2646.
6
7
8
. Ratnasamy S, Daniel C, Felipe Antonio S, et al. Bifunctional
organocatalysts in the asymmetric Michael additions of
carbonylic compounds to nitroalkenes. Curr Org Chem. 2012;
16:2440-2461.
. Aratake S, Itoh T, Okano T, et al. Highly diastereo- and
enantioselective direct aldol reactions of aldehydes and ketones
catalyzed by siloxyproline in the presence of water. Chem A
Eur J. 2007;13(36):10246-10256.
. Hernández JG, Juaristi E. Efficient ball-mill procedure in the
‘
green’ asymmetric aldol reaction organocatalyzed by (S)-pro-
line-containing dipeptides in the presence of water. Tetrahe-
ACKNOWLEDGEMENTS
dron. 2011;67:6953-6959.
This work was supported by Consejo Nacional de Ciencia
y Tecnología (CONACYT) (project 286620 and postdoc-
toral grants 170296 and 290754). J.M.H. Pérez would like
to acknowledge the computer resources, technical
expertise, and support provided by Laboratorio Nacional
de Supercómputo del Sureste de México, which is part
of the Consejo Nacional de Ciencia y Tecnología
9. Bhowmick S, Kunte SS, Bhowmick KC. The smallest
organocatalyst in highly enantioselective direct aldol reaction
in wet solvent-free conditions. RSC Adv. 2014;4:24311-24315.
0. Gao J, Bai S, Gao Q, Liu Y, Yang Q. Acid controlled dia-
stereoselectivity in asymmetric aldol reaction of cycloketones
with aldehydes using enamine-based organocatalysts. Chem
Commun. 2011;47(23):6716-6718.
11. Marco ABF, Luiz CD, Ives AL, Ellen CP, CdL E. Exploring the
aldol reaction in the synthesis of bioactive compounds. Curr
Org Synth. 2015;12:547-564.
1
(CONACYT) network of national laboratories.
1
2. Bhanushali M, Zhao C-G. Developing novel organocatalyzed
aldol reactions for the enantioselective synthesis of biologically
active molecules. Synthesis. 2011;2011(12):1815-1830.
3. Genc HN, Sirit A. Novel efficient bifunctional calixarene thio-
urea organocatalysts: synthesis and application in the direct
enantioselective aldol reactions. Tetrahedron Asymmetry. 2016;
27:201-207.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflicts of interest.
1
DATA AVAILABILITY STATEMENT
Data that support the findings of this study are available
in the supporting information of this article or are
available from the corresponding author upon reasonable
request.
14. List B, Lerner RA, Barbas CF. Proline-catalyzed direct asym-
metric aldol reactions. J Am Chem Soc. 2000;122:2395-2396.
1
5. Pearson AJ, Panda S. N-prolinylanthranilamide pseudopeptides
as bifunctional organocatalysts for asymmetric aldol reactions.
Org Lett. 2011;13(20):5548-5551.
ORCID
16. Wan W, Gao W, Ma G, et al. Asymmetric aldol reaction
organocatalyzed by bifunctional N-prolyl sulfinamides under
solvent-free conditions. RSC Adv. 2014;4(51):26563-26568.
Ratnasamy Somanathan https://orcid.org/0000-0003-
1
220-082X
Cecilia Anaya de Parrodi https://orcid.org/0000-0001-
619-2513
17. Fotaras S, Kokotos CG, Kokotos G. A tripeptide-like
prolinamide-thiourea as an aldol reaction catalyst. Org Biomol
Chem. 2012;10(29):5613-5619.
5
1
8. Revelou P, Kokotos CG, Moutevelis-Minakakis P. Novel
prolinamide–ureas as organocatalysts for the asymmetric aldol
reaction. Tetrahedron. 2012;68:8732-8738.
REFERENCES
1
. Jacoby CG, Vontobel PHV, Bach MF, Schneider PH. Highly
efficient organocatalysts for the asymmetric aldol reaction. New
J Chem. 2018;42:7416-7421.
19. Xu J, Fu X, Wu C, Simple HX. Inexpensive, and facile
L-prolinamide used as a recyclable organocatalyst for highly

HUELGAS ET AL.
15
efficient large-scale asymmetric direct aldol reactions. Tetrahe-
dron: Asymmetry. 2011;22:840-850.
of a chiral catalytic pocket. Org Biomol Chem. 2013;11(18):
2951-2960.
2
0. Hajos ZP, Parrish DR. Asymmetric synthesis of bicyclic inter-
mediates of natural product chemistry. J Org Chem. 1974;39:
34. Kitanosono T, Kobayashi S. Development of chiral catalysts for
Mukaiyama aldol reactions in aqueous media. The Chemical
Record. 2014;14(1):130-143.
1
615-1618.
2
2
1. Mukherjee S, Yang JW, Hoffmann S, List B. Asymmetric
enamine catalysis. Chem Rev. 2007;107(12):5471-5569.
35. Jimeno C. Water in asymmetric organocatalytic systems: a
global perspective. Org Biomol Chem. 2016;14(26):6147-6164.
36. Mlynarski J, Ba ꢀs S. Catalytic asymmetric aldol reactions in
aqueous media—a 5 year update. Chem Soc Rev. 2014;43(2):
577-587.
37. Min C, Seidel D. Asymmetric Brønsted acid catalysis with chi-
ral carboxylic acids. Chem Soc Rev. 2017;46(19):5889-5902.
38. Hong L, Sun W, Yang D, Li G, Wang R. Additive effects on
asymmetric catalysis. Chem Rev. 2016;116(6):4006-4123.
39. Bisticha A, Triandafillidi I, Kokotos CG. tert-Butyl esters of
peptides as organocatalysts for the asymmetric aldol reaction.
Tetrahedron Asymmetry. 2015;26:102-108.
40. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Scalmani G, Barone V, Mennucci B,
Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP,
Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M,
Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M,
Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgom-
ery, Jr. JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ,
Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R,
Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS,
Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE,
Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R,
Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C,
Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG,
Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD,
Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gauss-
ian 09. Revision D.01. Wallingford CT: Gaussian, Inc; 2013.
41. Zhurko GA. Chemcraft - graphical program for visualization of
quantum chemistry computations. Ivanovo, Russia, 2005.
https://chemcraftprog.com
2. Wang P, Li H-F, Zhao J-Z, Du Z-H, Da C-S. Organocatalytic
enantioselective cross-aldol reaction of o-hydroxyarylketones
and trifluoromethyl ketones. Org Lett. 2017;19(10):2634-2637.
3. Rojas Cabrera H, Huelgas G, Hernández Pérez JM, Walsh PJ,
Somanathan R, Anaya de Parrodi C. Homochiral l-
prolinamido-sulfonamides and their use as organocatalysts in
aldol reactions. Tetrahedron: Asymmetry. 2015;26:163-172.
4. Lygo B, Davison C, Evans T, Gilks JAR, Leonard J,
Roy C-E. Highly enantioselective aldol reactions using a
tropos dibenz[c,e]azepine organocatalyst. Tetrahedron. 2011;67:
2
2
2
1
0164-10170.
5. Bhowmick S, Mondal A, Ghosh A, Bhowmick KC. Water: the
most versatile and nature's friendly media in asymmetric
organocatalyzed direct aldol reactions. Tetrahedron Asymmetry.
2
015;26:1215-1244.
2
2
6. Snyder IE, Clement AR. Some syntheses and structures in the
9
,10-dihydro-9,10-ethanoanthracene series. J am Chem Soc.
1
960;82:1424-1427.
7. Fox ME, Gerlach A, Lennon IC, Meek G, Praquin C. A conve-
nient and scaleable synthesis of 11,12-diamino-9,10-dihydro-
9
,10-ethanoanthracene and its enantiomers. Synthesis. 2005;
2
005:3196-3198.
2
8. Tang Z, Yang Z-H, Chen X-H, Cun L-F, Mi A-Q, Jiang Y-Z. A
highly efficient organocatalyst for direct aldol reactions of
ketones with aldedydes. J am Chem Soc. 2005;127(25):9285-
9
289.
2
3
3
9. Gimeno MC, Herrera RP. Cover feature: hydrogen bonding
and internal or external Lewis or Brønsted acid assisted (thio)
urea catalysts. Eur J Org Chem. 2020;1057-1068.
0. Serdyuk OV, Heckel CM, Tsogoeva SB. Bifunctional primary
amine-thioureas in asymmetric organocatalysis. Org Biomol
Chem. 2013;11(41):7051-7071.
1. Kochetkov SV, Kucherenko AS, Zlotin SG. (1R,2R)-Bis[(S)-
prolinamido]cyclohexane modified with ionic groups: the first
C2-symmetric immobilized organocatalyst for asymmetric
aldol reactions in aqueous media. Eur J Org Chem. 2011;6128-
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
6
133.
3
3
2. Moteki SA, Maruyama H, Nakayama K, et al. Positive effect of
water in asymmetric direct aldol reactions with primary amine
organocatalyst: experimental and computational studies. Chem
Asian J. 2015;10(10):2112-2116.
How to cite this article: Huelgas G,
Somanathan R, Hernández Pérez JM, et al.
Homochiral bifunctional L-prolinamide- and L-bis-
prolinamide-catalyzed asymmetric aldol reactions
performed in wet solvent-free conditions. Chirality.
3. Delaney JP, Brozinski HL, Henderson LC. Synergistic effects
2
within a C -symmetric organocatalyst: the potential formation
2020;1–15. https://doi.org/10.1002/chir.23283