Novel primary amine organocatalysts derived from cinchona alkaloids for asymmetric direct aldol reactions in brine

Article abstract of DOI:10.1007/s10562-010-0478-x

A series of Cinchona alkaloids derived organocatalysts have been developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. The catalyzed reactions of various aldehydes and ketones gave the cor

Full text of DOI:10.1007/s10562-010-0478-x

Catal Lett (2011) 141:191–197
DOI 10.1007/s10562-010-0478-x
Novel Primary Amine Organocatalysts Derived from Cinchona
Alkaloids for Asymmetric Direct Aldol Reactions in Brine
•
•
•
Wen-Bo Huang Qing-Wen Liu Liang-Yu Zheng
Suo-Qin Zhang
Received: 21 July 2010 / Accepted: 18 October 2010 / Published online: 2 November 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of Cinchona alkaloids derived organ-
ocatalysts have been developed and evaluated in the direct
asymmetric intermolecular aldol reaction of 4-nitrobenz-
aldehyde and cyclohexanone. The catalyzed reactions of
various aldehydes and ketones gave the corresponding
aldol products with moderate to high enantioselectivities
(up to 92%) and diastereoselectivities (up to [99/1,
anti/syn) in the presence of 3e in brine.
reaction. Compared with the well-explored proline-based
organocatalysts, the development of efficient primary
amine organocatalysts is relatively sluggish. As we know, a
secondary enamine is better stabilized by hyper-conjuga-
tion, whereas a primary amine gives the predominant imine
form [21]. In a pioneering work by Amedikouh [22],
L-valine was successfully applied to the direct asymmetric
aldol reaction between aromatic aldehydes and acetone,
´
albeit the enantioselectivity was not high. Cordova et al.
Keywords Cinchona alkaloids Á Primary amine Á Aldol
reaction Á Brine
[23] found that acyclic primary amine acids such as ala-
nine, valine, and serine could efficiently catalyze the
asymmetric aldol reaction between aromatic aldehydes and
ketones with perfect enantioselectivity and moderate dia-
stereoselectivity. From then on, more and more primary
amino acids and primary amine-derived organocatalysts
were applied to this reaction [24–29].
1 Introduction
The asymmetric aldol reaction is one of the most popular
carbon–carbon bond-forming reactions [1–5] and plays an
important role in medicinal chemistry and natural products
synthesis. Development of organocatalysts for this reaction
has attracted a great deal attention [6–8]. Since the pio-
neering work by List, Barbas, and their co-workers [9–11],
numerous organocatalysts including proline-derived tetra-
zole [12], prolinol [13], proline N-sulfonyl amides [14],
proline-derived diamines [15, 16], proline-based small
peptides [17, 18] and proline amine alcohol amides [19, 20]
have been developed for the direct asymmetric aldol
On the other hand, the development of asymmetric
reactions in water is an attractive research field [30–33],
mainly due to the low cost, safety and environmentally
benign nature of water. Hayashi et al. [34, 35], Barbas et al.
[36], Pericas co-workers[37] and Gong et al. [38] have
reported proline-derived catalysts for the direct asymmetric
aldol reactions in the presence of water. However, reports
about primary amine catalyzed asymmetric aldol reaction
in aqueous medium are limited [39–46] (Fig. 1).
Herein we report a series of novel primary amine
organocatalysts 3a–3h for the asymmetric aldol reaction in
brine. These catalysts were synthesized from primary
amino acids and cinchona alkaloids derived amines. Cin-
chona alkaloids and their derivatives have tremendous
applications [47–54] in asymmetric catalysis. As hydrogen
bonding donor [16], the amide group of organocatalysts
3a–3h is crucial to the stabilization of the transition state
according to the Houk–List [55–57] model. To achieve
high stereo control, the incorporation of an appropriate
W.-B. Huang Á Q.-W. Liu Á S.-Q. Zhang (&)
College of Chemistry, Jilin University, Changchun,
Jilin 130012, People’s Republic of China
e-mail: suoqin@jlu.edu.cn
L.-Y. Zheng
Key Laboratory for Molecular Enzymology and Engineering
of Ministry of Education, Jilin University, Changchun, Jilin
130012, People’s Republic of China
123

192
W.-B. Huang et al.
Fig. 1 Examples of primary
amine organocatalysts for the
asymmetric direct aldol reaction
N
H2N
OTBSO
NH2
N
O
R
N
N
H
N
OH
H2N
Ph
N
NH2
H2N
HN
N
N
NH2
O
Bu-i
O
O
Ph
Ph
i-Bu
Ph
Pr-n H2N
N
N
N
N
H
H
OH
H
NHTf
H2N
H2N
OH
NH2
Ph
OH
Pr-n
Bu-
i
2.2 Catalyst Preparation
hydrophobic group into the organic catalyst is necessary as
it would generate a hydrophobic organocatalyst and
diminish the contact between the reaction transition state
and water. It was hypothesized that the cinchona alkaloids
backbone of the catalysts would play a double role in the
catalytic process. One role is to enhance steric shielding
[58], and another role is to enhance the hydrophobicity of
the catalysts to assembly with hydrophobic reactants and
sequester the transition state from water [59–61]. Catalysts
3a–3h were effective in the direct asymmetric aldol reac-
tion. Brine [62–66] was found to be the best solvent.
Organocatalysts 3a–3h were prepared from N-t-butyloxy-
carbonyl protected amino acids and cinchona alkaloids
derived amines. Take the synthesis of 3a for example.
N-t-Butyloxycarbonyl-L-alanine (1.1 mmol) and DCC
(1.1 mmol) were dissolved in 10 mL dichloromethane.
Then the solution was cooled to 0 °C and stirred for 0.5 h.
After that, 9-amino (9-deoxy) epicinchonine (1 mmol) was
added and the reaction mixture was warmed to room
temperature and stirred for another 12 h. After filtration
and the removal of solvent under reduced pressure, the
residue was purified through chromatography on silica gel
column [eluent, V (ethyl acetate)/V (triethyl amine) =10/1]
to afford compound 2 as a white solid.
2 Experimental
Compound 2 was dissolved in 2 mL dichloromethane, to
which 1 mL TFA was added. The solution was stirred for
5 h at room temperature. Then the reaction was quenched
with concentrated ammonia solution and extracted with
dichloromethane (3 9 10 mL). The organic layer was
washed with brine (2 9 10 mL), and dried over anhydrous
Na2SO4. After the removal of the solvent under reduced
pressure, the residue was purified through flash column
chromatography on silica gel (eluent, methanol) to afford
compound 3a as a white solid (Fig 2).
2.1 Materials and Instruments
Cinchona alkaloids (cinchonine, quinine), solvent and N-t-
butyloxycarbonyl protected amino acids were purchased
from commercial suppliers. Cinchona alkaloids derived
1
amines were synthesized according to literatures [47]. H
NMR spectra were recorded on a 300 MHz FT-NMR
Mercury-300B (Varian) spectrometer with tetramethylsil-
ane as an internal reference. Solvent for NMR is CDCl3.
13C NMR were recorded on 75 MHz. Elemental analyses
(C, H, and N) were performed on a Perkin-Elmer 2400
CHN Elemental Analyzer. The enantiomeric excess was
determined by chiral HPLC with Daicel Chiralpak AD–H
(4.6 9 250 mm2), OD–H (4.6 9 250 mm2) and AS–H
(4.6 9 250 mm2) column. Diastereoselectivities were
determined by 1H NMR analysis of the aldol product,
Scheme 1.
2.2.1 Catalyst 3a
1H NMR (300 MHz, CDCl3), d: 0.89–1.01 (m, 1H), 1.30
(d, J = 6.9 Hz 3H), 1.38–1.57 (m, 3H), 2.28–2.33 (m, 1H),
2.92–3.14 (m, 5H), 3.47 (q, J = 6.9 Hz, 6.9 Hz, 1H),
5.11–5.16 (m, 2H), 5.39 (brs, 1H), 5.86–5.93 (m, 1H), 7.38
Scheme 1 Preparation of
organocatalysts. Take the
synthesis of 3a for example
O
O
N
N
NH
NHBoc
N
H2N
NH
O
NH2
TFA
DCC
OH
CH2Cl2
CH2Cl2
NHBoc
N
N
N
2
1
3a
123

Primary Amine Organocatalysts from Cinchona Alkaloids
193
Fig. 2 Organocatalysts
evaluated in this study
(d, J = 4.8 Hz, 1H), 7.57–7.63 (m, 1H), 7.69–7.75 (m,
1H), 7.99 (brs, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.39 (d,
J = 8.1 Hz, 1H), 8.87 (d, J = 4.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3), d: 21.36, 25.36, 26.42, 27.09, 39.01,
46.85, 49.03, 50.49, 59.61, 114.56, 118.96, 123.19, 126.30,
127.04, 128.79, 130.06, 140.06, 147.01, 148.30, 149.67,
175.40; (EI) m/z 365 (rel. intensity) (M??1); Analysis
calculated for C22H28N4O: C, 72.50; H, 7.74; N, 15.37.
Found: C, 72.62; H, 7.66; N, 15.28.
calculated for C23H30N4O2: C, 70.02; H, 7.66; N, 14.20.
Found: C, 70.11; H, 7.59; N, 14.28.
2.2.4 Catalyst 3d
1H NMR (300 MHz, CDCl3), d: 0.81–0.85(m, 1H), 1.12
(d, J = 6.9 Hz, 3H), 1.52–1.65 (m, 4H), 2.26–2.30 (m, 1H),
2.63–2.76 (m, 2H), 3.17–3.28 (m, 3H), 3.47 (q, J = 5.6,
5.6 Hz, 1H), 3.93 (s, 3H), 4.94–5.01 (m, 2H), 5.43 (brs,
1H), 5.70–5.81 (m, 1H), 7.24 (d, J = 4.5 Hz,1H),
7.31–7.35 (m, 1H), 7.63 (s, 1H), 7.81 (brs, 1H), 7.95 (d,
J = 9.3 Hz, 1H), 8.68 (d, J = 4.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3), d: 21.575, 26.536, 27.374, 27.81, 39.43,
40.99, 50.75, 55.62, 56.06, 59.33, 101.93, 114.41, 119.30,
121.64, 128.37, 131.63, 141.33, 144.76, 147.40, 157.78,
175.37; (EI) m/z 395 (rel. intensity) (M??1); Analysis
calculated for C23H30N4O2: C, 70.02; H, 7.66; N, 14.20.
Found: C, 70.15; H, 7.70; N, 14.18.
2.2.2 Catalyst 3b
1H NMR (300 MHz, CDCl3), d: 0.85–1.02 (m, 1H), 1.31
(d, J = 6.9 Hz 3H), 1.38–1.56 (m, 3H), 2.27–2.34 (m, 1H),
2.82–3.14 (m, 6H), 3.46 (q, J = 6.9 Hz, 6.9 Hz, 1H),
5.09–5.17 (m, 2H), 5.33 (brs, 1H), 5.85–5.97 (m, 1H), 7.41
(d, J = 4.8 Hz, 1H), 7.62 (t, J = 7.5 Hz,1H), 7.74 (t,
J = 6.9 Hz, 1H), 8.01 (brs, 1H), 8.14 (d, J = 8.7 Hz, 1H),
8.39 (d, J = 8.4 Hz, 1H), 8.88 (d, J = 4.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3), d: 20.99, 25.13, 26.12, 26.83,
38.69, 46.57, 48.76, 50.25, 59.31, 114.23, 118.65, 123.02,
126.01, 126.77, 128.54, 129.73, 139.83, 146.76, 148.01,
149.41, 175.17; (EI) m/z 365 (rel. intensity) (M??1);
Analysis calculated for C22H28N4O: C, 72.50; H, 7.74; N,
15.37. Found: C, 72.58; H, 7.70; N, 15.42.
2.2.5 Catalyst 3e
1H NMR (300 MHz, CDCl3), d: 0.56–0.59(d, J = 6.9 Hz
3H), 0.86–0.89 (d, J = 6. 9 Hz 3H), 1.57–1.68 (m, 5H),
2.14–2.19 (m, 1H), 2.30–2.32 (m, 1H), 2.69–2.79 (m, 2H),
3.24–3.34 (m, 4H), 3.98 (s, 3H), 4.98–5.04 (m, 2H), 5.55
(brs, 1H), 5.73–5.85 (m, 1H), 7.30–7.31 (m, 1H), 7.35–7.39
(m, 1H), 7.72 (s, 1H), 8.02 (d, J = 9 Hz, 1H), 8.73 (d,
J = 4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3), d: 15.82,
19.48, 26.54, 27.21, 27.63, 30.91, 39.27, 40.93, 49.49,
55.49, 55.89, 59.43, 59.97, 101.6, 114.33, 118.36, 121.84,
128.52, 131.39, 141.25, 144.55, 147.20, 157.69, 174.21;
(EI) m/z 423 (rel. intensity) (M??1); Analysis calculated
for C25H34N4O2: C, 71.06; H, 8.11; N, 13.26. Found: C,
71.21; H, 8.09; N, 13.33.
2.2.3 Catalyst 3c
1H NMR (300 MHz, CDCl3), d:0.86–0.91 (m, 1H), 1.17 (d,
J = 6.9 Hz, 3H), 1.57–1.7 (m, 4H), 2.30–2.35 (m, 1H),
2.68–2.80 (m, 2H), 3.22–3.33 (m, 3H), 3.49 (q, J = 5.6,
5.6 Hz, 1H), 3.98 (s, 3H), 4.99–5.05 (m, 2H), 5.50 (brs,
1H), 5.74–5.86 (m, 1H), 7.29 (d, J = 4.5 Hz,1H),
7.35–7.39 (m, 1H), 7.68 (s, 1H), 7.86 (brs, 1H), 7.99
(d, J = 9.3 Hz, 1H), 8.73 (d, J = 4.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3), d: 21.318, 26.56, 27.17, 27.48, 39.11,
40.86, 50.53, 55.44, 55.80, 59.04, 101.66, 114.31, 119.01,
121.69, 128.28, 131.36, 141.06, 144.55, 147.16, 157.71,
175.24; (EI) m/z 395 (rel. intensity) (M??1); Analysis
2.2.6 Catalyst 3f
1H NMR (300 MHz, CDCl3), d: 0.82 (d, J = 6.9 Hz 3H),
0.91 (d J = 6.9 Hz 3H), 1.57–1.68 (m, 5H), 2.15–2.31
123

194
W.-B. Huang et al.
(m, 2H), 2.64–2.76 (m, 2H), 3.12–3.26 (m, 4H), 3.98
(s, 3H), 4.96–5.03 (m, 2H), 5.43 (brs, 1H), 5.72–5.84
(m, 1H), 7.32 (d, J = 4.5 Hz,1H), 7.35–7.39 (m, 1H), 7.72
(s, 1H), 7.99 (d, J = 9.3 Hz, 1H), 8.72 (d, J = 4.5 Hz,
1H); 13C NMR (75 MHz, CDCl3), d:16.22, 19.49, 26.56,
27.35, 27.72, 31.28, 39.34, 40.94, 50.27, 55.58, 55.90,
59.05, 60.42, 101.93, 114.34, 118.95,121.69, 128.41,
131.45, 141.30, 144.64, 147.25, 157.77, 173.99; (EI) m/z
423 (rel. intensity) (M??1); Analysis calculated for
C25H34N4O2: C, 71.06; H, 8.11; N, 13.26. Found: C, 71.18;
H, 8.15; N, 13.45.
ethyl acetate (10 mL 9 3). Combined organic layer and
dried over anhydrous Na2SO4. After the removal of the
solvent under reduced pressure, the residue was purified
through flash column chromatography on silica gel [eluent,
V (ethyl acetate)/V (petroleum ether) =3:1] to afford pure
aldol product.
3 Results and Discussion
Initially catalysts 3a, 3b, 3c and 3d were prepared and their
catalytic activities were evaluated in the model reaction
between 4-nitrobenzaldehyde and cyclohexanone at room
temperature. It was found that enantioselectivities and
diastereoselectivities were low (Table 1, entries 1–4), the
performance of catalysts 3b (derived from R-alanine and
2.2.7 Catalyst 3g
1H NMR (300 MHz, CDCl3), d: 0.84 (q, 6H), 1.13–1.22
(m, 1H), 1.52–1.68 (m, 7H), 2.31–2.32 (m, 1H), 2.68–2.78
(m, 2H), 3.22–3.44 (m, 4H), 3.98 (s, 3H), 4.98–5.04
(m, 2H), 5.48 (brs, 1H), 5.73–5.85 (m, 1H), 7.29–7.31
(d, J = 4.5 Hz,1H), 7.35–7.39 (m, 1H), 7.68 (s, 1H), 8.02
(d, J = 9.3 Hz, 1H), 8.74 (d, J = 4.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3), d: 21.13, 23.01, 24.42, 26.51,27.15,
27.56, 39.21, 40.83, 43.80, 49.40, 53.24, 55.40, 55.83,
59.14, 101.54, 114.23, 118.54,121.68, 128.32, 131.31,
141.19, 144.47, 147.15, 157.61, 175.18; (EI) m/z 437 (rel.
intensity) (M??1); Analysis calculated for C26H36N4O2:
C, 71.53; H, 8.31; N, 12.83. Found: C, 71.65; H, 8.17; N,
12.75.
Table 1 Aldol reaction of cyclohexanone and 4-nitrobenzaldehyde
under various conditions
OH
O
O
O
H
cat
O2N
O2N
6
4
5
Entry Solvent Catalyst Time
(h)
Yield
(%)A
Anti/
synB
ee for anti
(%)C
1
2
Neat
Neat
Neat
Neat
3a
3b
3c
3d
12
13
13
15
45
47
52
72
15
12
17
45
19
28
30
27
28
91
93
90
92
82
85
88
trace
90
96
94
82
93
92
88
85
87
89:11
70:30
92:8
85:15
78:22
86:14
90:10
–
40
60
75
45
54
48
57
–
2.2.8 Catalyst 3h
3
1H NMR (300 MHz, CDCl3), d: 0.86 (q, 6H), 1.33–1.39
(m, 1H), 1.60–1.68 (m, 7H), 2.29–2.34 (m, 1H), 2.70–2.77
(m, 2H), 3.20–3.33 (m, 4H), 3.98 (s, 3H), 4.96–5.03
(m, 2H), 5.39 (brs, 1H), 5.72–5.83 (m, 1H), 7.32–7.33
(d, J = 4.5 Hz, 1H), 7.35–7.39 (m, 1H), 7.71 (s, 1H),
7.86(brs, 1H), 7.99 (d, J = 9.3 Hz, 1H), 8.72
(d, J = 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3), d:
21.40, 23.14, 24.65, 26.55, 27.32, 27.69, 39.29, 40.95,
44.10, 51.03, 53.55, 55.62, 55.90, 59.16, 101.91, 114.46,
119.16, 121.75, 128.39, 131.49, 141.22, 144.66, 147.31,
157.84, 175.12; (EI) m/z 437 (rel. intensity) (M??1);
Analysis calculated for C26H36N4O2: C, 71.53; H, 8.31; N,
12.83. Found: C, 71.53; H, 8.18; N, 12.88.
4
5
CH2Cl2 3c
CHCl3 3c
Toluene 3c
6
7
8
DMF
Water
Brine
3c
3c
3c
3c
3c
3c
3e
3f
9
87:13
95:5
94:6
92:8
97:3
74
84
84
81
86
10
11D Brine
12E Brine
13F Brine
14F Brine
15F Brine
16F Brine
17F Brine
[99:1 92
94:6
97:3
95:5
76
89
82
3g
3h
2.3 General Procedure for the Catalytic Direct
Asymmetric Aldol Reaction
Conditions: aldehyde (0.25 mmol), cyclohexanone (2.5 mmol), cat-
alyst (5 mol%), 1.5 mL brine, RT
A
Isolated yield
All solvents were refined according to standard methods.
Aldehyde, cyclohexanone (freshly distilled), catalyst and
1.5 mL solvent were added to a 5 mL glass reactor. The
reaction mixture was stirred until all the aldehyde has been
consumed (monitored by TLC). Quenched with saturated
ammonium chloride solution (5 mL), and extracted with
B
Determined by chiral HPLC
1
Determined by H NMR
C
D
E
F
3 mol% of catalyst used
1 mol% of catalyst used
Reaction temperature 5 °C, 3 mol% of catalyst used
123

Primary Amine Organocatalysts from Cinchona Alkaloids
195
cinchonine) and 3c (derive from S-alanine and quinine)
was superior to 3a (derived from S-alanine and cinchonine)
and 3d (derived from R-alanine and quinine), 3c gave the
best result. We supposed that the match of chirality
between amino acids and Cinchona alkaloids was crucial to
enantioselectivity, the two chiral elements of catalysts 3b
and 3c matched better over catalysts 3a and 3d [58],
enhancing the stereo control of the organocatalyzed direct
aldol reaction. Then, various solvents (entries 5–10) were
screened with 3c at room temperature. Brine [61] was
found to be the more suitable solvent, good yield and
diastereoselectivity were obtained albeit the enantioselec-
tivity was not satisfying (entry 10). Influence of catalyst
loading was also examined. Reducing the amount of cat-
alyst (entry 11) from 5 to 3 mol% did not cause the drop of
yield and enantioselectivity. Further lowering the loading
to 1 mol% resulted in decreased enantioselectivity and
yield. The enantioselectivity increased (84–86%) slightly
as the reaction temperature decreased from room temper-
ature to 5 °C. The performance of catalyst 3c under opti-
mized reaction condition (entry 13) was still not satisfying.
Hence, analogues 3e, 3f, 3g and 3h were synthesized and
applied to the model reaction under the optimized condi-
tion in the hope of achieving good enantioselectivity.
Results were showed in Table 1 (entries 14–17). Catalyst
3e gave the best result (ee up to 92%, dr [99:1). Under the
same conditions, catalysts 3e and 3g gave the desired
product in higher enantioselectivity and diastereoselectiv-
ity, catalysts 3f and 3g gave the desired product in lower
enantioselectivity and diastereoselectivity. The results
indicated that S-amino acids matched better with Quinine,
and the alkyl substituents at the chiral carbon atom influ-
enced the enantioselectivity.
Table 2 Aldol reaction of various aldehydes and cyclohexanone in
the presence of 3e
O
O
5
OH
6
O
H
cat
R
R
4
Entry R
Product Time Yield
(%)A
Anti/
synB
ee for anti
(%)C
(h)
1
4-NO2
6a
6b
6c
6d
6e
6f
28
30
42
32
72
72
96
96
96
96
96
72
72
92
[99:1 92
[99:1 83
[99:1 90
[99:1 87
2
3-NO2
2-NO2
4-CN
3-CN
2-CN
4-Cl
90
3
93
4
93
5
82
98:2
[99:1 83
96:4 62
67
6
88
7
6g
6h
6i
71
8
3-Cl
68
[99:1 47
[99:1 55
90:10 60
[99:1 45
9
2-Cl
65
10
11
12
13
4-F
6j
68
2-F
6k
6l
70
H
Trace
Trace
–
–
–
–
4-CH3O
6m
Conditions: aldehyde (0.25 mmol), cyclohexanone (2.5 mmol),
catalyst (3 mol%), 1.5 mL brine, reaction temperature 5 °C
A
Isolated yield
B
Determined by chiral HPLC
1
Determined by chiral HNMR
C
of benzaldehyde and 4-methoxybenzaldehyde with cyclo-
hexanone afforded trace product under the same reaction
condition.
We also examined the direct asymmetric aldol reactions
between various ketones and aldehydes as shown in Table 3.
The aldol reaction of cyclopentanone with 4-nitrobenzal-
dehyde gave the corresponding aldol product in moderate
yield but with low enantioselectivity and diastereoselectiv-
ity. The reactions of acetone with 4-nitrobenzaldehyde and
3-nitrobenzaldehyde afforded the aldol product in moderate
yield with low enantioselectivity.
To further explore the scope of the reaction, the direct
asymmetric aldol reactions of various aldehydes and
cyclohexanone in the presence of 3e were examined as
shown in Table 2. We selected methoxy substituent as a
representative electron-donating group, nitro-, cyano-, flu-
oro-, and chloro- substituents as an electron-withdrawing
group on the benzene ring. The benzaldehydes substituted
by strong electron-withdrawing nitro- and cyano- groups
(except 3-cyanobenzaldehyde) were converted to the cor-
responding aldol products in high yields, with moderate to
high enantioselectivities (83–92% ee) and perfect diaste-
reoselectivities (dr [99:1). Enantioselectivity was influ-
enced by the position of substituent (entries 1 and 2),
4-nitrobenzaldehyde was converted to the corresponding
aldol product with 92% ee value, however, 3-nitrobenzal-
dehyde only with 83% ee value. The aldol reactions of less
reactive benzaldehydes which bearing chloro- and fluoro-
substituents on the benzene ring (entries 7–11) were very
sluggish, giving the corresponding aldol product in mod-
erate yields with moderate enantioselectivities. Reactions
4 Conclusion
In summary, a series of novel primary amine organocata-
lysts have been developed and applied to the asymmetric
direct aldol reactions, 3e was found to be the best catalyst.
3 mol% of 3e is enough to efficiently promote the aldol
reaction of various aromatic aldehydes and cyclohexanone
with moderate to high enantioselectivities (up to 92%) and
diastereoselectivities (up to [99:1) in brine. Applications
of these catalysts in asymmetric transformations are in
progress in our laboratory.
123

196
W.-B. Huang et al.
Table 3 Aldol reaction of aldehydes and various ketones in the presence of 3e
O
OH
O
O
cat
H
R1
R2
R
R
R1
R2
4
5
6
Entry
R
R1
R2
Product
Time (h)
Yield (%)A
anti/synB
ee (%)C
1
2
3
4-NO2
2-NO2
4-NO2
-(CH2)3-
CH3-
6n
6o
6p
49
42
37
63
72
75
80:20
45
47
41
H
H
–
–
CH3-
Conditions: aldehyde (0.25 mmol), ketone (2.5 mmol), catalyst (3 mol%), 1.5 mL brine, reaction temperature 5 °C
A
Isolated yield
B
Determined by chiral HPLC
1
Determined by chiral HNMR
C
References
28. Zheng B-L, Liu Q-Z, Guo C-S, Wang X-L, He L (2007) Org
Biomol Chem 5:2913
29. Peng F-Z, Shao Z-H, Pu X-W, Zhang H-B (2008) Adv Synth
Catal 350:2199
30. Mlynarski J, Paradowska J (2008) Chem Soc Rev 37:1502
31. Pan CF, Wang ZY (2008) Coord Chem Rev 252:736
32. Gruttadauria M, Giacalone F, Noto R (2009) Adv Synth Catal
351:33
33. Mase N, Barbas CF III (2010) Org Biomol Chem 8:4043
34. Hayashi Y, Sumiya T, Takahashi J (2006) Angew Chem Int Ed
45:958
1. Mahrwald R (ed) (2004) Modern aldol reactions, vol 1 and 2.
Wiley-VCH, Weinheim
´ ´
2. Guillena G, Najera C, Ramon DJ (2007) Tetrahedron Asymmetry
18:2249
3. Geary LM, Hultin PG (2009) Tetrahedron Asymmetry 20:131
4. Zlotin SG, Kucherenko AS, Beletskaya IP (2009) Russ Chem
Rev 78:737
5. Trost BM, Brindle CS (2010) Chem Soc Rev 39:1600
6. List B (2004) Acc Chem Res 37:548
35. Hayashi Y, Aratake S, Okano T (2006) Angew Chem Int Ed
45:5527
36. Mase N, Nakai Y, Ohara N, Yoda H, Takabe K, Tanaka F, Barbas
CF III (2006) J Am Chem Soc 128:734
`
37. Font D, Jimeno C, Pericas MA (2006) Org Lett 8:4653
38. Chen X-H, Luo S-W, Tang Z (2007) Chem Eur J 13:689
7. Notz W, Tanaka F, Barbas CF III (2004) Acc Chem Res 37:580
8. Mukherjee S, Yang JW, Hoffmann S, List B (2007) Chem Rev
107:5471
9. List B, Lerner RA, Barbas CF III (2000) J Am Chem Soc
122:2395
10. Notz W, List B (2000) J Am Chem Soc 122:7386
11. Sakthivel K, Notz W, Bui T, Barbas CF III (2001) J Am Chem
Soc 123:5260
´
39. Cordova A, Zou W-B, Dziedzic P, Ibrahem I, Reyes E, Xu Y-M
(2006) Chem Eur J 12:5383
40. Tanaka F, Thayumanavan R, Mase N (2004) Tetrahedron Lett
45:325
12. Torii H, Nakadai M, Ishihara K, Saito S, Yamamoto H (2004)
Angew Chem Int Ed 43:1983
41. Amedjkouh M (2007) Tetrahedron Asymmetry 18:390
42. Pizzarello S, Weber AL (2004) Science 303:1151
43. Zhu M-K, Xu X, Gong L-Z (2008) Adv Synth Catal 350:1390
44. Miura T, Yasaku Y (2009) Tetrahedron Lett 50:2632
45. Teo YC, Lee PPF (2009) Synth Commun 39:3081
46. Ma X, Da C-S, Yi L (2009) Tetrahedron Asymmetry 20:1419
47. Brunner H, Bu¨gler J, Nuber B (1995) Tetrahedron Asymmetry
7:1699
13. Zhong G-F, Fan J-H, Barbas CF III (2004) Tetrahedron Lett
45:5681
14. Berkessel A, Koch B, Lex J (2004) Adv Synth Catal 346:1141
15. Nakadai M, Saito S, Yamamoto H (2002) Tetrahedron 58:8167
16. Mase N, Tanaka F, Barbas CF III (2004) Angew Chem Int Ed
43:2420
17. Revell JD, Wennemers H (2007) Tetrahedron 63:8420
18. Luppi G, Giorgio CP, Monari M, Kaptein B, Broxterman QB,
Tomasini C (2005) J Org Chem 70:7418
19. Tang Z, Jiang F, Yu L-T, Cui X, Gong LZ, Mi A-Q, Jiang Y-Z,
Wu W-D (2003) J Am Chem Soc 125:5262
48. Chen Y-G, McDaid P, Deng L (2003) Chem Rev 103:2965
49. Tian S-K, Chen Y-C, Hang J, Tang L, McDaid P, Deng L (2004)
Acc Chem Res 37:621
50. Connon SJ (2008) Chem Commun 2499
51. Chen YC (2008) Synlett 13:1919–1930
´
52. Palomo C, Oiarbide M, Lopez R (2009) Chem Soc Rev
38:632
20. Tang Z, Yang Z-H, Chen X-H, Cun L-F, Mi A-Q, Jiang Y-Z,
Gong L-Z (2005) J Am Chem Soc 127:9285
21. Xu L-W, Lu Y-X (2008) Org Biomol Chem 6:2048
22. Amedikouh M (2005) Tetrahedron Asymmetry 16:1411
53. Enders D, Wang C, Liebich JX (2009) Chem Euro J 15:11058
54. Marcelli T, Hiemstra H (2010) Synthesis 8:1229–1279
55. Bahmanyar S, Houk KN (2001) J Am Chem Soc 123:12911
56. Hoang L, Bahmanyar S, Houk KN, List B (2003) J Am Chem Soc
125:16
´
23. Cordova A, Zou W-B, Ibrahem I, Reyes E, Engqvist, Liao W-W
(2005) Chem Commun 3586
24. Xu LW, Luo J, Lu YX (2009) Chem Commun 1807
25. Wu X-Y, Jiang Z-Q, Shen H-M, Lu Y-X (2007) Adv Synth Catal
349:812
57. Bahmanyar S, Houk KN, Martin HJ, List B (2003) J Am Chem
Soc 125:2475
26. Luo S-Z, Xu H, Li J-Y, Zhang L, Cheng J-P (2007) J Am Chem
Soc 129:3074
58. Chen J-R, An X-L, Zhu X-Y, Wang X-F, Xiao W-J (2008) J Org
Chem 73:6006
27. Liu J, Yang Z, Wang Z, Wang F, Chen X-H, Liu X-H, Feng X-M,
Su Z-S, Hu C-W (2008) J Am Chem Soc 130:5654
123

Primary Amine Organocatalysts from Cinchona Alkaloids
197
59. Mase N, Nakai Y, Ohara N, Yoda H, Takabe K, Tanaka F, Barbas
CF III (2005) J Am Chem Soc 128:735
60. Mase N, Watanabe K, Yoda H, Takabe K, Tanaka F, Barbas CF
III (2006) J Am Chem Soc 128:4967
61. Maya V, Raj M, Singh VK (2007) Org Lett 9:2593
62. Shinisha CB, Sunoj RB (2007) Org Biomol Chem 5:1287
63. Gandhi S, Singh VK (2008) J Org Chem 73:9411
64. Huang W-P, Chen J-R, Li X-Y, Cao Y-J, Xiao W-J (2007) Can J
Chem 85:208
65. Moorthy JN, Saha S (2009) Eur J Org Chem 2009:739
66. Jia Y-N, Wu F-C, Ma X, Zhu G-J, Da C-S (2009) Tetrahedron
Lett 50:3059
123