Rational combination of two privileged chiral backbones: Highly efficient organocatalysts for asymmetric direct aldol reactions between aromatic aldehydes and acylic ketones

Article abstract of DOI:10.1021/jo800910s

(Figure Presented) A new class of organocatalysts has been designed by rational combination of proline with cinchona alkaloids. The chiral amine 3a, prepared from L-proline and cinchonidine, has been found to be an efficient catalyst for the direct aldol reactions of acetone or 2-butanone with a wide range of aldehydes (up to 98% ee). The cinchonidine backbone is essential to the reaction efficiency and enantioselectivity.

Full text of DOI:10.1021/jo800910s

provide straightforward access to the optically active ꢀ-hydroxy
carbonyl structural unit found in many natural products drugs,6
have received remarkable attention. Since the pioneering work
by Barbas,7a List,7b,c and co-workers that L-proline could act
as an efficient catalyst for direct aldol reaction between acetone
and aldehydes, a number of proline derivatives have been
developed for this enantioselective transformation.2c,8,9 Accord-
ing to the Houk-List model10 and Gong’s work9c,d the hydrogen
bonding donor in proline and its analogues is crucial to the
catalytic activity and selectivity. In our continuing efforts to
develop readily tunable and highly enantioselective organocata-
lysts,11 we recently designed a series of bifunctional organo-
catalysts based on the proline catalysis concept and double
hydrogen bonding activation. For example, the catalysts 1 and
2 show superior catalytic activities for the aldol reactions
Rational Combination of Two Privileged Chiral
Backbones: Highly Efficient Organocatalysts for
Asymmetric Direct Aldol Reactions between
Aromatic Aldehydes and Acylic Ketones
Jia-Rong Chen, Xiao-Lei An, Xiao-Yu Zhu, Xu-Fan Wang,
and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry
of Education, College of Chemistry, Central China Normal
UniVersity, 152 Luoyu Road, Wuhan, Hubei 430079, China
wxiao@mail.ccnu.edu.cn
ReceiVed April 27, 2008
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C. F., III Angew. Chem., Int. Ed. 2008, 47, 42.
A new class of organocatalysts has been designed by rational
combination of proline with cinchona alkaloids. The chiral
amine 3a, prepared from L-proline and cinchonidine, has been
found to be an efficient catalyst for the direct aldol reactions
of acetone or 2-butanone with a wide range of aldehydes
(up to 98% ee). The cinchonidine backbone is essential to
the reaction efficiency and enantioselectivity.
(9) For representative examples of organocatalytic aldol reactions, see:(a)
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Since 2000, the capacity to catalyze enantioselective trans-
formations with organic small molecules has remained a focal
point for extensive research efforts in the field of asymmetric
catalysis.1 In particular, the use of chiral secondary amine as
catalysts has proven to be a powerful protocol for stereoselective
functionalizations of carbonyl compounds.2–5 In this active
research field, the asymmetric direct aldol reactions, which
(1) (a) For general reviews on organocatalysis, see : Dalko, P. I.; Moisan, L.
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6006 J. Org. Chem. 2008, 73, 6006–6009
10.1021/jo800910s CCC: $40.75 2008 American Chemical Society
Published on Web 06/24/2008

SCHEME 1. Direct Aldol Reaction of Cycloketones with
Aldehydes
between a variety of cycloketones and aldehydes, and in many
cases the ratio of diastereoisomers (anti:syn) is greater than 99:1
and ee is greater than 99% (Scheme 1).11a,b We also found that
a subtle modification in the catalyst structure, which results in
the change in pKa value of the catalyst, has substantial effect
on the enantioselectivity and suggest that the double hydrogen
bondings play an important role in tuning the catalytic activity.
However, the utilization of these catalysts in the aldol reaction
of acyclic ketones with aldehydes only gave moderate results.
Our objective, therefore, for the continued advancement of this
field is the design of distinct catalysts that enable previously
unsuccessful transformations.
Cinchona alkaloids and their derivatives have been success-
fully applied in a wide diversity of organocatalytic reactions,12
acting as chiral-base,13 phase-transfer,14 and nucleophilic cata-
lysts.15 Given their extraordinary capacity revealed in various
chemical transformations, we envisaged that rational incorpora-
tion of the stereocontrolling elements of proline and cinchona
alkaloid in a single molecule would lead to a new class of chiral
organocatalysts (Figure 1).16 Herein, we demonstrate that these
FIGURE 1. Key design elements of a new class of chiral amine
catalysts.
TABLE 1. Direct Aldol Reaction of 4-Nitrobenzaldehyde 7a with
Acetone 8a Catalyzed by Organocatalysts 3-6a
entry
catalyst
solvent
time (h)
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
3a
3b
4a
4b
5
acetone
acetone
acetone
acetone
acetone
acetone
CHCl3
CH2Cl2
THF
Et2O
EtOH
MeOH
DMF
brine
0.5
2
2
4
5
1.5
1.5
1
1
1.5
4
89
89
87
79
73
94
87
90
84
96
87
95
84
71
87
85
14
66
2
-11
-86
49
64
58
61
58
59
63
6
3a
3a
3a
3a
3a
3a
3a
3a
3a
9
10
11
12
13
14
15
1
3
4
3
(11) (a) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J.
Org. Lett. 2005, 7, 4543. (b) Chen, J.-R.; Li, X.-Y.; Xing, X.-N.; Xiao, W.-J. J.
Org. Chem. 2006, 71, 8198. (c) Huang, W.-P.; Chen, J.-R.; Li, X.-Y.; Cao, Y.-
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H.; Lai, Y.-Y.; Lu, L.-Q.; Xiao, W.-J. Synthesis 2006, 3795. (f) Li, D.-P.; Guo,
Y.-C.; Ding, Y.; Xiao, W.-J. Chem. Commun. 2006, 799. (g) Cao, Y.-J.; Lai,
Y.-Y.; Wang, X.; Xiao, W.-J. Tetrahedron Lett. 2007, 48, 21. (h) Chen, J.-R.;
Liu, X.-P.; Zhu, X.-Y.; Li, L.; Qiao, Y.-F.; Xiao, W.-J. Tetrahedron 2007, 63,
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J. Angew. Chem., Int. Ed. 2008, 47, 2489. (j) Lu, L.-Q.; Cao, Y.-J.; Liu, X.-P.;
An, J.; Yao, C.-J.; Ming, Z.-H.; Xiao, W.-J. J. Am. Chem. Soc. 2008, 130, 6946.
(12) For general reviews, see:(a) Kacprzak, K.; Gawroski, J. Synthesis 2001,
961. (b) Chen, Y.; McDaid, P.; Deng, L. Chem. ReV. 2003, 103, 2965. (c) Tian,
S.-K.; Chen, Y.-C.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res.
2004, 37, 621.
55
53
H2O
a Reactions were carried out with 0.3 mmol of 7a and 0.5 mL of
acetone and 0.5 mL of solvent in the presence of 10 mol % of catalyst
and 20 mol % of HOAc. b Determined by chiral HPLC.
organic molecules indeed show good to excellent enantioselec-
tivities (up to 98% ee) in the direct aldol reaction of acetone
and 2-butanone with aldehydes.
The organocatalysts 3-6 (Figure 1) were synthesized from
commercially available L-proline (or D-proline) and cinchona
alkaloids (see Supporting Information). Noteworthy, such type
of catalyst features a big chiral backbone and one tertiary
quinuclidine nitrogen, which could form an ion pair with acid
additive to give another tunable hydrogen bonding donor (Figure
1). The catalytic performance of the catalyst was then evaluated
in the direct asymmetric aldol reaction of 4-nitrobenzaldehyde
7a with acetone 8a.
As can be seen from the results summarized in Table 1, the
catalysts 3-6 can efficiently catalyze the direct aldol reaction
of aldehyde 7a and acetone 8a with variant ee values. It should
be noted that the rational combination of the L-proline with
cinchona alkaloids is critical to the stereocontrolling in the aldol
reaction (Table 1, entries 1-4). The bifunctional catalysts 3a
and 4a, derived from L-proline, cinchonidine, and quinine,
(13) For some recent examples, see: (a) Bartoli, G.; Bosco, M.; Carlone, A.;
Locatelli, M.; Melchiorre, P.; Sambri, L. Angew. Chem., Int. Ed. 2005, 44, 6219.
(b) Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc. 2005,
127, 14566. (c) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 2896. (d) Poulsen, T. B.; Alemparte,
C.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614. (e) Lou, S.; Taoka,
B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256. (f) Wang,
Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (g) Wang, Y.; Li, H.;
Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391. (h) Cantarero, J.-L.; Cid, M.-b.;
Poulsen, B.-T.; Bella, M.; Ruano, J. L. G.; Jørgensen, K. A. J. Org. Chem. 2007,
72, 7062. (i) Guo, C.; Xue, M.-X.; Zhu, M.-K.; Gong, L.-Z. Angew. Chem., Int.
Ed. 2008, 47, 3414.
(14) (a) Ooi, T; Maruoka, K. Acc. Chem. Res. 2004, 37, 526. (b) O’Donnell,
M. J. Acc. Chem. Res. 2004, 37, 506. (c) Lygo, B.; Andrews, B. I. Acc. Chem.
Res. 2004, 37, 518. (d) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013. (e)
Hashimoto, T.; Maruoka, K. Chem. ReV. 2007, 107, 5656.
(15) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003,
103, 2985.
(16) For a comment on “privileged chiral catalysts”, please see: Yoon, T. P.;
Jacobsen, E. N. Science 2003, 299, 1691.
J. Org. Chem. Vol. 73, No. 15, 2008 6007

TABLE 2. Effects of the Acid Additives on the Catalytic
Performance of Catalyst 3aa
TABLE 3. Aldol Reaction between 7 and 8a Catalyzed by
Catalyst 3aa
entry
R
9
temp (°C)
yield (%)
ee (%)b
entry
HX
y (mol %) time (h) yield (%) ee (%)b
1
2
3
4
5
6
7
8
4-NO2-Ph (7a)
4-NO2-Ph (7a)
3-NO2-Ph (7b)
2-NO2-Ph (7c)
4-NC-Ph (7d)
4-Br-Ph (7e)
4-Cl-Ph (7f)
2-Cl-Ph (7g)
2,4-Cl2-Ph (7h)
4-CF3-Ph (7i)
4-F-Ph (7j)
9a
9a
9b
9c
9d
9e
9g
9h
9i
-30
-40
-30
-30
-40
-30
-30
-30
-30
-40
-15
-40
r.t.
85
97
94
80
60
90
95
89
84
93
69
87
61
82
61
<5
89
96
94
89
90
92
93
97
93
89
78
87
90
87
85
90
80
88
77
1
2
3
4
5
6
7
8
none
HCl
12
16
79
71
58
65
58
20
53
86
68
85
70
84
NR
NR
81
89
82
73
68
85
49
42
57
57
57
ND
64
67
64
72
32
80
10
10
10
10
10
10
10
10
10
10
10
20
30
10
20
30
40
100
20
NCCO2H
ClCH2CO2H
Cl3CCO2H
p-TsOH
3,5-2NO2PhCO2H
PhCO2H
TFA
4.5
4.5
4.5
24
4.5
0.5
4.5
4.5
4.5
4.5
9
10
11
12
13
14
15
16
17c
18c
19c
20c
9j
9k
9l
9
10
11
12
13
14
15
16
17
18
19
CF3SO3H
HBr
3,4-F2-Ph (7k)
Ph (7l)
3-PhO-Ph (7m)
2-furyl (7n)
9m
9n
9o
9o
9a
9b
9c
9d
HClO4
HClO4
HClO4
HOAc
HOAc
HOAc
HOAc
HOAc
-30
24
24
0.5
0.5
0.5
0.5
0.5
-5
i-Pr (7o)
r.t.
74
85
79
77
69
90
4-NO2-Ph (7a)
3-NO2-Ph (7b)
2-NO2-Ph (7c)
4-NC-Ph (7d)
-30
-30
-30
-30
-93
-94
-97
-90
20c HOAc
23
a Unless otherwise noted, the reactions were carried out with 0.3
mmol of 7 in 1.0 mL of acetone with 10 mol % of catalyst 3a and 20
mol % of HOAc for 23-96 h. b Determined by chiral HPLC. c With 6
as the catalyst.
a Unless otherwise noted, reactions were carried out with 0.3 mmol of
7a and 1.0 mL of acetone in the presence of 10 mol % of catalyst and x
mol
% of cocatalyst HX. ND: not determined. NR: no reaction.
b Determined by chiral HPLC. c Performed at -30 °C.
TABLE 4. Aldol Reaction between 7a-c and 8b Catalyzed by
Catalyst 3aa
showed better enantioselectivities over their pseudoenantiomers,
3b and 4b, respectively (Table 1, entries 1 vs 2, 3 vs 4). When
the scaffold of D-proline was introduced to the catalyst backbone,
the opposite enantiomer of the aldol product was obtained than
with low ee values (Table 1, entry 5). As anticipated, the catalyst
6 (pseudoenantiomer of 3a) induced higher enantioselectivity
than 5, giving the product with opposite configuration with 86%
ee (Table 1, entries 6 vs 5). We then tested different solvents
with 3a as the catalyst. An enantioselectivity/solvent profile
indicated that the reaction in acetone proceeded with better ee
values than in other solvents (Table 1, entries 7-15).
It is well-known that the Brønsted acid additive should be
involved in the intricate iminium-enamine equilibrium, and it
can also play an important role in the activation of the aldol
acceptor by hydrogen bonding. Therefore, a series of Brønsted
acids have been examined as the cocatalyst in the direct
asymmetric aldol reaction of 4-nitrobenzaldehyde (7a) with
acetone (8a) (Table 2). An enantioselectivity/cocatalyst profile
reveals that optimal enantiocontrol can be achieved when acetic
acid or perchloric acid is employed as the cocatalyst (Table 2,
entries 12 and 15). Further examinations document that the
reaction efficiency as well as the enantioselectivity can be
improved if the ratio of HOAc to 3a is 2:1. Variation of this
ratio proved detrimental to the reaction (Table 2, entries 15,
17-19 vs 16) and the superior level of asymmetric induction
and efficiency could be reached when the reaction was
performed at -30 °C with catalyst 3a and HOAc (Table 2, entry
20, 85% yield and 90% ee).
entry
R
product
yield (%)
drb
ee (%)c
1
2
3
4
5
6
4-NO2-Ph (7a)
10a
11a
10b
11b
10c
11c
32
53
26
71
54
39
75
98
82
92
94
92
93:7
93:7
96:4
3-NO2-Ph (7b)
2-NO2-Ph (7c)
a Unless otherwise noted, the reactions were carried out with 0.3
mmol of 7 in 1.0 mL of 2-butanone (8b) with 20 mol % of catalyst 3a
and 40 mol
%
of HOAc for 48 h. b Determined by 1H NMR
spectroscopy. anti/syn. c Determined by chiral HPLC for the
anti-product.
97% ee). Heteroaromatic aldehyde, for example, 2-furaldehyde
(7n), reacts smoothly with acetone under optimal conditions to
yield the corresponding aldol product in good enantioselectivity
(Table 3, entry 15). However, aliphatic aldehydes exhibited
much lower reactivity in this transformation. The reaction of
isobutaldehyde (7o) with acetone proceeds very slowly ac-
companied by a small amount of dehydrated product (Table 3,
entry 16). Notably, the opposite enantiomeric aldol product can
also be obtained with high ee values when amine 6/HOAc is
used as the catalyst under the same conditions (Table 3, entries
17-20).
With the optimized conditions in hand, we then examined
the scope of the aldehyde substrate in the aldol reaction of
acetones (Table 3). The reaction appears quite tolerant with
respect to the steric contribution of the substituent in substituted
benzaldehydes and the desired products could be obtained in
good yields with good to excellent enantioselectivities (up to
The reaction of nitro-substituted benzaldehyde with 2-bu-
tanone (8b) was also investigated to examine the scope of the
aldol donors. As shown in Table 4, in the case of 4- and 3-nitro-
substituted benzaldehydes, the reaction preferentially occurred
at the C-3 position to furnish the aldol adducts 11a,b as the
major products in remarkably high diastereoselectivities (dr 93:
6008 J. Org. Chem. Vol. 73, No. 15, 2008

7) and enantioselectivities (98% and 92% ee, respectively)
(Table 4, entries 2 and 4). Interestingly, the reaction of
2-nitrobenzaldehyde and 8b mainly took place at the C-1
position to afford the aldol product 10c as the major product in
excellent enantioselectivity (Table 4, entry 5, 94% ee). In
addition, we have also preliminarily examined the feasibility
of using cyclic ketones as aldol donors using 3a as the catalyst.
In the case of cyclohexanone (8c), excellent diastereoselectivtiy
(93:7 dr) for anti-isomer (12) was obtained; however, the ee
value of anti-isomer was somewhat low compared to that of
catalysts 1 and 2 (eq 11).11 Further extension of the reaction
scope of aldehyde acceptors with 2-butanone is underway in
our laboratory.
Experimental Section
Representative Procedure for the Direct Aldol Reaction of
Aldehyde 7 with Acetone 8a. The organocatalyst 3a (0.03 mmol)
and HOAc (0.06 mmol) were stirred in 1 mL of acetone for 20
min at the indicated temperature. The corresponding aldehyde 7
(0.3 mmol) was added and the mixture was stirred for 23-96 h.
The mixture was then treated with 10 mL of saturated ammonium
chloride solution and extracted with ethyl acetate. The combined
organic layer was dried over MgSO4, filtered, and concentrated to
give pure aldol product 9 after flash column chromatography on
silica gel (petroleum ether/ethyl acetate (3:1)).
4-Hydroxy-4-(4′-nitrophenyl)-butan-2-one (9a). The ee was
determined by HPLC (Chiralpak AS column, hexane/i-PrOH 70:
30, flow rate 1 mL/min; tR(minor) ) 13.6 min; tR(major) ) 16.4
1
min, λ ) 254 nm). H NMR (400 MHz, CDCl3) δ 2.23 (s, 3H),
2.85-2.87 (m, 2H), 3.67 (d, J ) 2.4 Hz, 1H), 5.26-5.28 (m, 1H),
7.54 (d, J ) 8.8 Hz, 2H), 8.21 (d, J ) 10.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 30.6, 51.4, 68.7, 123.6, 126.3, 147.1, 149.9,
208.6.
Acknowledgment. We are grateful to the National Science
Foundation of China (20672040), the National Basic Research
Program of China (2004CCA00100), the Program for New
Century Excellent Talents in University (NCET-05-0672), and
the Cultivation Fund of the Key Scientific and Technical
Innovation Project (Ministry of Education of China, No 705039)
for support of this research.
In conclusion, we have developed a new class of organo-
catalysts, which were prepared from commercially available and
inexpensive proline and cinchona alkaloids, for the asymmetric
direct aldol reactions of acetone and 2-butanone with aldehydes.
High isolated yields (up to 97%) and enantioselectivities (up to
98% ee) were obtained by using these catalysts. Stereoselective
formation of both enantiomers can be achieved through selection
of catalysts 3a or 6, which are pseudoenantiomers. The present
studies have demonstrated the key role of combination of
privileged chiral backbone and hydrogen bonding interactions
in the asymmetric aldol reaction. We hope that this strategy
will give some hints in the further design of organocatalysts
for other asymmetric reactions.
Supporting Information Available: Experimental proce-
dures, characterization of new compounds, 1HMR and 13CNMR
spectra of new compounds, and HPLC spectra of aldol products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO800910S
J. Org. Chem. Vol. 73, No. 15, 2008 6009