C2-symmetric bisprolinamide as a highly efficient catalyst for direct aldol reaction

Article abstract of DOI:10.1021/ol052277f

(Chemical Equation Presented) The catalytic activity of the prolinamide-type catalysts may be improved by introducing additional prolinamide moiety into the catalyst, while the enantioselectivity can still be maintained or further improved. A C₂

Full text of DOI:10.1021/ol052277f

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5321-5323
C2-Symmetric Bisprolinamide as a
Highly Efficient Catalyst for Direct Aldol
Reaction
Sampak Samanta, Jinyun Liu, Rajasekhar Dodda, and Cong-Gui Zhao*
Department of Chemistry, UniVersity of Texas at San Antonio,
6900 North Loop 1604 West, San Antonio, Texas 78249-0698
cong.zhao@utsa.edu
Received September 20, 2005
ABSTRACT
The catalytic activity of the prolinamide-type catalysts may be improved by introducing additional prolinamide moiety into the catalyst, while
the enantioselectivity can still be maintained or further improved. A C2-symmetric bisprolinamide with two prolinamide moieties has been
found to be an excellent catalyst for direct aldol reaction with more than doubled reactivity and better asymmetric induction than its
monoprolinamide counterpart.
The aldol reaction is an important tool in organic synthesis
due to its usefulness in synthesizing â-hydroxy carbonyl
compounds, which are subunits of many natural products.1
Direct aldol reaction does not require preformed enolate, and
therefore, it is more convenient to carry out and is highly
atomically economic. Although highly enantioselective tran-
sition-metal catalysts have been developed,2 there have been
many efforts directed toward developing highly efficient
organocatalysts for this reaction in recent years,3 since
environmentally benign methods are currently in vogue.4
Since the early discovery of List and Barbas that L-proline
may be used as the catalyst for the enantioselective direct
aldol reaction,5 several proline-derivatives have been syn-
thesized and applied for highly enantioselective direct aldol
(3) (a) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem.,
Int. Ed. 2005, 44, 3055. (b) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen,
K. A. Chem. Commun. 2002, 620. (c) Northrup, A. B.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 124, 6798. (d) Northrup, A. B.; Mangion, I.
K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43,
2152. (e) Sekiguchi, Y.; Sasaoka, A.; Shimomoto, A.; Fujioka, S.; Kotsuki,
H. Synlett 2003, 11, 1655. (f) Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg.
Med. Chem. Lett. 2003, 13, 2445. (g) Saito, S.; Nakadai, M.; Yamamoto,
H. Synlett 2001, 1245. (h) Nakadai, M.; Saito, S.; Yamamoto, H.
Tetrahedron 2002, 58, 8167. (i) Torii, H.; Nakadai, M.; Ishihara, K.; Saito,
S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. (j) Saito, S.;
Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
(1) Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 229-275.
(4) (a) Anastas, P.; Warner, J. Green Chemistry: Theory and Practice;
Oxford University Press: Oxford, 1998. (b) Anastas, P. T.; Kirchhoff, M.
M. Acc. Chem. Res. 2002, 35, 686.
(2) (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (b)
Trost, B. M.; Ito, H.; Shilcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367.
(c) Trost, B. M.; Shin, S.; Sclafani, J. A. J. Am. Chem. Soc. 2005, 127,
8602. (d) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (e) Shibasaki, M.; Kanai,
M.; Funabashi, K. Chem. Commun. 2002, 1989. (f) Kumagai, N.; Matsunaga,
S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169. (g) Mahrwald, R. Org.
Lett. 2000, 2, 4011. (h) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am.
Chem. Soc. 2003, 125, 8706.
(5) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395. (b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (c)
List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (d) Sakthivel,
K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123,
5260. (e) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem. Int.
Ed. 2003, 42, 2785. (f) List, B. Synlett 2001, 1675. (g) List, B. Tetrahedron
2002, 58, 5573. (h) List, B. Acc. Chem. Res. 2004, 37, 548. (j) Martin, H.
J.; List, B. Synlett 2003, 1901. (a) Notz, W.; Tanaka, F.; Barbas, C. F., III.
Acc. Chem. Res. 2004, 37, 580
10.1021/ol052277f CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/06/2005

reaction.3,5,6 However, the catalytic activity of these catalysts
is normally quite low; to achieve a good yield in reasonable
time, large loading of the catalyst (20-30 mol %) is required.
Most recently, Gong and co-workers reported a very promis-
ing prolinamide catalyst 1 (Figure 1), which yields very high
enantioselectivity.6,7 Catalysts 3-5 may be readily prepared
from N-carbobenzyloxy-L-proline and corresponding diamine
in just two steps. To verify our hypothesis, monoprolinamide
catalyst 6 was also synthesized for comparison.
Table 1. Direct Aldol Reaction of 4-Nitrobenzaldehyde and
Acetone Catalyzed by Catalysts 3-6a
Figure 1. Gong’s prolinamide catalysts1 and 2.
entry
catalyst
time (h)
T (°C)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9e
3
4
5
5
5
5
5
6
1
1.5
1.5
1.5
7
12
12
5
rt
rt
rt
94
93
93
91
90
88
75d
35d
66
22
45
68
77
89
98
98
98
93
enantioselectivities for the aldol products when 20 mol %
of 1 is used in the reactions.6 While our work was still in
progress, the same group reported a new catalyst 2 with much
improved reactivity through finely tuning the electronic
effects.7
Besides the electronic effects that can be utilized to
improve the catalyst reactivity, we envisioned that the
reactivity might be improved by incorporating more than one
prolinamide moiety into the catalyst structure to generate a
catalyst with multiple reaction centers, based on the hypoth-
esis that the chance for the substrate to meet with the reaction
center increases when the number of the reaction centers is
increased. Herein, we wish to report a C2-symmetric bispro-
linamide catalyst that has retained the asymmetric induction
power of its monoprolinamide counterpart but with more than
doubled reactivity.8
0
-25
-35
-35
-35
-25
5
24
a All reactions were performed with 0.25 mmol of 4-nitrobenzaldehyde
and anhydrous acetone (0.5 mL) using 10 mol % of the catalyst. b Yield of
isolated product after column chromatography. c Enantiomeric excess was
determined by HPLC; absolute configuration of the major enantiomer was
determined by comparing the measured optical rotation with the reported
data.6 d Conversions; determined by 1H NMR spectroscopy. e Taken from
ref 6c, with 20 mol % of catalyst 1.
Indeed, these catalysts show very high reactivity (Table
1). For example, with 10 mol % of catalyst 3, the reaction
of 4-nitrobenzaldehyde and acetone finished within 1.5 h at
room temperature with high yield (entry 1). The ee value
was nonetheless very low (22%). After phenyl groups were
introduced into the diamine moiety, the two diastereomeric
catalysts 4 and 5 maintained high reactivity, yet the enan-
tioselectivities were increased, with catalyst 5 better than 4
(entries 2 and 3). The reaction conditions were further
optimized for catalyst 5 to increase the enantioselectivity,
and it was found that the enantioselectivity was dependent
on temperature: The ee value of the aldol product increases
while the reaction temperature is lowered (entries 3-5), and
the best ee value was obtained at -35 °C (98% ee, entry 6).
Although monoprolinamide catalyst 6 also induces the same
level of enantioselectivity, it is clear that it has only half of
the reactivity of that of 5 (entries 7 and 8). Catalyst 5 is also
more reactive than similar monoprolinamide catalyst 1,6 since
only half the amount of the catalyst and half the reaction
time is required to achieve an even better yield than 1 (entries
6 and 9).
Figure 2. C2-Symmetric bisprolinamide catalysts 3-5 and mono-
prolinamide catalyst 6.
In our design of catalyst with two prolinamide moieties,
to achieve uniformity of asymmetric induction of the two
reaction centers, we introduced C2-symmetry. Thus, we
synthesized C2-symmetric bisprolinamide catalysts 3,9 4, and
5 (Figure 2). In these catalysts, each reaction center has a
remote amide hydrogen to promote the reactivity and
To test the substrate generality of this new catalyst, the
reaction of various aldehydes with acetone was studied under
(6) (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Gong, L.-Z.; Mi, A.-Q.; Jiang,
Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. (b) Tang, Z.; Yang,
Z.-H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6,
2285. (c) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-
Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5755. (d) Guo,
H.-M.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem. Commun.
2005, 1450.
(7) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang,
Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285.
(8) While our paper was under revision, Xiao published a related work
of bifunctional prolinamide catalyst, see: Chen, J.-R.; Lu, H.-H.; Li, X.-
Y.; Chen, L.; Wan, J.; Xiao, W.-J. Org. Lett. 2005, 7, 4543.
(9) Catalyst 3 is a known compound; see: Alco´n, M. J.; Iglesias, M.;
Sa´nchez, F.; Viani, I. J. Organomet. Chem. 2000, 284.
5322
Org. Lett., Vol. 7, No. 23, 2005

the optimized conditions. The results are summarized in
Table 2. As shown in Table 2, aldehydes with nitro
Scheme 1. Direct Aldol Reaction of 4-Nitrobenzaldehyde and
Some Ketones Catalyzed by Catalyst 5
Table 2. Direct Aldol Reaction of Vaious Aldehydes and
Acetone Catalyzed by Catalyst 5
entry
R
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
2,6-Cl2C6H3
4-CNC6H4
Ph
88
86
81
79
81
74
85
71
69
65
52
57
78
98
89
93
93
96
89
86
82
90
93
96
98
97
Cyclohexanone yielded a dr of 97:3 for the anti/syn products,
with an ee of 93% for the major product (upper equation).
It is interesting to note that catalysts 5 and 26d have the
opposite preference for these two substrates in terms of
enantioselectivity. Acetol gave a mixture of the two regio-
isomers, and the regioisomer of the less stable enamine has
an ee value of 97% (lower equation).
Besides the fact that the catalyst loading may be reduced
from 20 to 10 mol %, bisprolinamide catalyst 5 leads to
higher enantioselectivities and yields than the corresponding
monoprolinamide catalyst 16 in most cases. The improved
performance in enantioselectivity is probably due to the
replacement of the hydroxy hydrogen in 1 by an amide
hydrogen in catalyst 5, since the hydrogen-bonding ability
of this remote hydrogen atom is crucial to achieve high
enantioselectivity.6,7
In summary, C2-symmetric bisprolinamide 5 has been
found to be an excellent catalyst for direct aldol reaction.
The catalytic activity of the prolinamide-type catalysts may
be improved by introducing additional reaction center(s) into
the catalyst, while the enantioselectivity can still be main-
tained or further improved. Further tuning of the reactivity
and enantioselectivity of catalyst 5 via electronic effects is
currently underway.
4-MeC6H4
4-MeOC6H4
Me3C
c-C6H11
a All of the reactions were conducted with the aldehyde (0.25 mmol)
and catalyst 5 (0.025 mmol) in anhydrous acetone (0.5 mL) at -35 °C for
12-24 h (48 h for entries 11-13). b Yield of isolated product after column
chromatography. c Enantiomeric excess was determined by HPLC; absolute
configuration of the major enantiomer was determined by comparing the
measured optical rotation with the reported data.6,7
substitution all gave very good yields of the aldol products
with excellent ee values (entries 1-3). Similarly, halogenated
benzaldehydes all produced very good ee values and yields
(entries 4-7). 4-Cyanobenzaldehyde gave the lowest ee value
among all the aldehydes studied, yet the ee value was still
good (entry 8). Aromatic aldehydes with electron-donating
groups led to slightly inferior yields, but the enantioselec-
tivities were excellent (entries 9-11). Aliphatic aldehydes
are also good substrates for this reaction: Sterically demand-
ing 2,2-dimethylpropanal (entry 12) led to a high enantiose-
lectivity of 98%; similarly, cyclohexanecarbaldehyde also
produced a high ee value of 97% (entry 13). It is worth noting
that 4-methoxybenzaldehyde yielded the aldol products with
96% ee (entry 11), which is the highest ee value achieved
so far for such a substrate.10
Acknowledgment. The generous financial support of this
research from the Welch Foundation (Grant No. AX-1593)
is gratefully appreciated.
We also studied some other ketone substrates (Scheme
1). Cyclopentanone gave a dr of of 40:60 for the anti/syn
products; with ee value of 82% and 18% ee, respectively.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all new compounds and HPLC
analysis data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) Previously the highest ee value achieved for this substrate was 82%;
see: Ayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. Tetrahedron Lett. 2004,
45, 4353.
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