New N-terminal prolyl-dipeptide derivatives as organocatalysts for direct asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2006.08.084

A series of new N-terminal prolyl-dipeptide derivatives have been synthesized and evaluated as organocatalysts for the direct asymmetric aldol reaction of acetone with electron-deficient aromatic aldehydes. At room temperature, the presence of 10 mol % of

Full text of DOI:10.1016/j.tetlet.2006.08.084

Tetrahedron Letters 47 (2006) 7793–7796
New N-terminal prolyl-dipeptide derivatives as organocatalysts
for direct asymmetric aldol reaction
Ji-Fu Zheng, Yao-Xian Li, Suo-Qin Zhang,* Song-Tao Yang, Xiao-Ming Wang,
Yong-Zhi Wang, Jie Bai and Fu-An Liu
College of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130023, PR China
Received 17 June 2006; revised 22 August 2006; accepted 23 August 2006
Available online 18 September 2006
Abstract—A series of new N-terminal prolyl-dipeptide derivatives have been synthesized and evaluated as organocatalysts for the
direct asymmetric aldol reaction of acetone with electron-deficient aromatic aldehydes. At room temperature, the presence of
10 mol % of catalysts 2 and 5 efficiently catalyzes the direct asymmetric aldol reaction to give the aldol adducts with modest to excel-
lent enantiomeric excesses (ee) values, which are up to 96%.
Ó 2006 Elsevier Ltd. All rights reserved.
The aldol reaction is one of the most powerful carbon–
carbon bond formation methods in organic synthesis.1
Since List et al. demonstrated that L-proline itself could
catalyze the intermolecular direct asymmetric aldol reac-
tion,2 the concept of small organic molecules as catalysts
has received considerable attention and asymmetric
organocatalysis has become a new and intriguing field
in synthetic chemistry.3 Proline and several proline-
derived catalysts have been developed for the direct
asymmetric aldol reaction,4–13 such as pyrrolidinyl-
tetrazole,6 benzoimidazole–pyrrolidine,7 and L-prolin-
amide derivatives.8–10 Though the pyrrolidinyltetrazole
and benzoimidazole–pyrrolidine increase the reactivity
and expand the solvent scope of the direct asymmetric
aldol reaction, no obvious improvement in enantioselec-
tivity has been achieved as compared to that of L-pro-
line. At low temperatures, most of the L-prolinamide
derivatives are often able to catalyze intermolecular ke-
tone aldolization with high enantioselectivity. Small
peptides can be ideal asymmetric organocatalysts
because of their diversified structures and functionality.
But only a few successful examples catalyzed by the
small peptides for direct aldol reactions have been
reported.11 Based on N-terminal prolyl dipeptides, we
replaced C-terminal carboxylic acid by tetrazole and
benzoimidazole, which can lead to higher acidity and
solubility of the catalysts to improve the reactivity and
selectivity of the reaction. Herein, we wish to report
the applications of five new N-terminal prolyl-dipeptide
derivatives 1–5 in the direct aldol reaction between ace-
tone and electron-deficient aromatic aldehydes at room
temperature.
Catalysts 1–5 (shown in Fig. 1) were readily prepared
from N-carbobenzyloxy-L-proline and the correspond-
ing a-amino acid tetrazole and a-aminobenzoimidazole
by the known reaction sequences in just two steps
(see the Supplementary data),14–16 and to afford the
product (for example, 2) in 52% total yield based on
N-carbobenzyloxy-L-proline. The structure of 1 was
confirmed by single X-ray crystallographic analysis
(see the Supplementary data).
Keywords: Organocatalyst; N-terminal prolyl-dipeptide derivatives;
Direct aldol reaction; Asymmetric catalysis.
*
Corresponding author. Tel./fax: +86 431 8499845; e-mail: suoqin@
jlu.edu.cn
Figure 1. The chiral organocatalysts 1–5.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.084

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J.-F. Zheng et al. / Tetrahedron Letters 47 (2006) 7793–7796
Table 1. Direct aldol reaction of acetone and 4-nitrobenzaldehyde
catalyzed by catalysts 1–3
(Table 1, entries 6–8). Our experimental results also indi-
cated that catalyst 3 (Table 1, entry 11) could tolerate
the presence of 10% of water with the ee values of the
products remaining at moderate level.
Interestingly, the addition of triethylamine (Et3N) with
an equal molar amount of catalyst slightly improved
the reaction yield and the enantioselectivity as compared
to that with the catalysts in the absence of additives
(Table 1, entry 4, 60% yield with 92% ee vs entry 12,
64% yield with 96% ee). However, while the loading of
Et3N was increased to 200% molar amount of catalyst,
the ee value of aldol adduct was decreased (Table 1,
entry 13).
Entry Catalyst Solvent
Catalyst Yielda (%) eeb (%)
(mol %)
1
2
3
4
5
6
7
8
9
10
11
12
13
1
2
3
2
2
2
2
2
1
2
3
2
2
DMF
DMF
DMF
DMF
DMF
DMSO
20
20
20
10
10
10
51
68
43
60
20
64
40
75
67
61
63
64
64
86
96
88
92
74c
82
90
59
42
46
67
96e
86f
1,4-Dioxane 10
To investigate the scope of the substrate of catalyst 2,
the reactions of various aromatic aldehydes with ace-
tone were studied under the optimized conditions (using
10 mol % of 2 as catalyst, in the presence of 10 mol %
Et3N). As shown in Table 2, the reactions of various
aromatic aldehydes, which bear an electron-withdraw-
ing group on the benzene ring, proceeded smoothly in
excellent enantioselectivities (up to 96%) to furnish the
aldol adducts (Table 2, entry 2). In addition, halogen-
ated benzaldehydes led to decreased yields. Interest-
ingly, the ee values of the products remained at good
levels (Table 2, entries 7–9). On the other hand, this
catalytic system was proven to be completely ineffective
for the aromatic aldehydes with an electron-donating
group or without any substitution (Table 2, entries 10
and 11).
THF
10
DMF/H2Od 10
DMF/H2Od 10
DMF/H2Od 10
DMF
DMF
10
10
a Isolated yield after silica gel column chromatography.
b The ee values were determined by HPLC analyses (Daicel Chiralpack
AS-H ) with hexane/2-propanol as the eluent.
c The reaction was performed at À25 °C.
d The mixture of (9:1) (DMF/water) was employed as a solvent, the
reaction time was 18 h.
e The reaction was performed in the presence of 10 mol % Et3N.
f The reaction was performed in the presence of 20 mol % Et3N.
First, at room temperature, we evaluated the catalytic
properties of catalysts 1–3 in N,N-dimethylformamide
(DMF). As an initial test run, the aldol reaction between
acetone and 4-nitrobenzaldehyde was examined, and the
results are summarized in Table 1. Compared to catalyst
1, catalysts 2 and 3 led to aldol adduct with high enantio-
selectivity (Table 1, entry 1 vs 2 and 3) which could be
attributed to the introduction of the other chiral center
in catalysts 2 and 3. Catalyst 2 gave aldol adduct with
excellent enantioselectivity and ee value up to 96%
(Table 1, entry 2) in comparison to that of catalyst 3.
This result is presumably due to the steric bulk of their
substituted groups, which plays an important role in the
stereo-control. Moreover, it is noteworthy that even
Next, in order to increase the solubility of the catalysts,
we replaced the C-terminal carboxylic acid with benz-
imidazole to gain two new dipeptide derivatives 4 and
5. Using 4 and 5 as catalysts, we examined the reaction
of 4-nitrobenzaldehyde with neat acetone under various
conditions and the experimental results are listed in
Table 2. Direct aldol reaction of acetone and various aromatic
aldehydes catalyzed by catalyst 2
loading of catalyst
2 was reduced from 20 to
10 mol %, there is no significant change in yield or selec-
tivity (Table 1, entry 2 vs 4).
Entry R1
Product Et3N (mol %) Yielda (%) eeb (%)
1
2
3
4
5
6
7
8
9
4-NO2 6a
None
10
None
10
None
10
10
10
10
10
10
60
64
62
69
51
62
46
45
92
96
76
82
74
86
83c
76c
84c
n.d.c,d
n.d.c,d
It is well known that temperature exerts a significant
effect on the enantioselectivity of the direct asymmetric
aldol reaction. In most cases, the enantioselectivities of
catalysts ascend with decreasing temperature. However,
as seen in Table 1, entries 4 and 5, ee value of the aldol
adduct was decreased at lower temperature. Therefore,
the room temperature condition was appropriate for
the direct aldol reaction of 4-nitrobenzaldehyde and ace-
tone and the best ee value was up to 96% ee (Table 1,
entry 2).
4-NO2 6a
2-NO2 6b
2-NO2 6b
4-CN
4-CN
4-Cl
2-Cl
4-Br
4-H
6c
6c
6d
6e
6f
49
Traces
Traces
10
11
6g
4-CH3 6h
a Isolated yield after flash column chromatography on silica gel.
b The ee values were determined by HPLC analyses (Daicel Chiralpack
AS-H) with hexane/2-propanol as the eluent.
c Reaction time was 48 h.
We also examined the solvent effect in this reaction. It
was found that dimethylsulfoxide (DMSO), 1,4-dioxane
and tetrahydrofuran (THF) were also suitable solvents
for the direct asymmetric aldol reaction besides DMF
d Not determined.

J.-F. Zheng et al. / Tetrahedron Letters 47 (2006) 7793–7796
7795
Table 3. Direct aldol reaction of acetone and 4-nitrobenzaldehyde
catalyzed by catalysts 4 and 5
10 mol %, while the catalyst loadings of other dipeptide
catalysts were usually from 20 to 40 mol %.
In summary, five new N-terminal prolyl-dipeptide deriv-
atives 1–5 have been first synthesized and applied as cat-
alysts for the direct asymmetric intermolecular aldol
reaction. The experimental results showed the reaction
with moderate to excellent enantioselectivity at room
temperature. Among these new catalysts, catalyst 2 is
the most efficient one for the direct aldol reaction
between acetone and electron-deficient aromatic alde-
hydes, which produces aldol products with 76–96% ee
values under the optimized conditions. Catalyst 5 also
shows a significant catalytic activity for the aldol reac-
tion of 4-nitrobenzaldehyde with neat acetone in good
yields and high enantioselectivities (up to 96% ee).
Further investigation of catalyst 5 is in progress.
Entry Catalyst Catalyst Time (h) Yielda (%) eeb (%)
(mol %)
1
2
3
4
4
5
5
5
10
10
5
48
24
24
24
32
73
60
26
59
96
90
57c
10
a Isolated yield after flash column chromatography on silica gel.
b The ee values were determined by HPLC analyses (Daicel Chiralpack
AS-H) with hexane/2-propanol as the eluent.
c The reaction was performed at À25 °C.
Table 3. It was found that catalyst 5 showed significant
catalytic activity to produce the aldol adduct with good
yield and enantioselectivity, while catalyst 4 led to poor
yield and enantioselectivity (Table 3, entry 2, 73% yield
with 96% ee vs entry 1, 32% yield with 59% ee). More-
over, when the reaction was carried out under the same
condition with only 5 mol % catalyst loading of 5, the
aldol product was also obtained in high enantioselectiv-
ity (Table 3, entry 3). Similar to catalyst 2, the reaction
catalyzed by 5 also resulted in poor yield and low
enantioselectivity at low temperature (Table 3, entry 4,
26% yield with 57% ee).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.08.084.
References and notes
1. (a) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002,
1595–1601; (b) Mestres, R. Green Chem. 2004, 6, 583–603;
´
(c) Palomo, C.; Oiarbide, M.; Garcıa, J. M. Chem. Soc.
Rev. 2004, 33, 65–75.
2. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem.
Soc. 2000, 122, 2395–2396.
3. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
40, 3726–3748; (b) Dalko, P. I.; Moisan, L. Angew. Chem.,
Int. Ed. 2004, 43, 5138–5175.
4. (a) List, B. Acc. Chem. Res. 2004, 37, 548–557; (b) Saito,
S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570–579; (c)
Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res.
2004, 37, 580–591.
5. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem.
Soc. 2000, 122, 2395–2396; (b) Sakthivel, K.; Notz, W.;
Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123,
5260–5267; (c) Northrup, A. B.; Casas, J.; Sunden, H.;
Finally, we studied the direct aldol reaction of 4-nitro-
benzaldehyde and cyclopentanone catalyzed by catalysts
2 and 5 (Scheme 1). In the case of catalyst 2, the reaction
was carried out for 6 h to afford the desired products in
good yield and dr for the syn/anti products was 65:35
with ee value of 56% and 77%, respectively. The reaction
catalyzed by 5 gave higher yield than that catalyzed by 2
up to 96%. The dr for the syn/anti products was 89:11
with ee value of 29% and 79%, respectively.
Our studies show that the enantioselectivities of cata-
lysts 1–5 were remarkably improved for introducing
the nitrogen-containing heterocyclic groups, compared
to dipeptide catalysts H-Pro-Gly-OH,11c H-Pro-Ala-
OH,11d and H-Pro-Phe-OH.11e Moreover, the catalyst
loading of our dipeptide derivatives may be reduced to
´
Cordova, A. Tetrahedron Lett. 2004, 45, 6117–6119; (d)
Chandrasekhar, S.; Narsihmulu, Ch.; Reddy, N. R.;
Sultana, S. S. Tetrahedron Lett. 2004, 45, 4581–4582.
6. (a) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
2004, 15, 1983–1986; (b) Hartikka, A.; Arvidsson, P. I.
Eur. J. Org. Chem. 2005, 4287–4295.
7. Lacoste, E.; Landais, Y.; Schenk, K.; Verlhac, J.-B.;
Vincent, J.-M. Tetrahedron Lett. 2004, 45, 8035–8038.
8. (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Mi, A.-Q.; Jiang, Y.-Z.;
Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262–5263; (b)
Tanimori, S.; Naka, T.; Kirihata, M. Synth. Commun.
2004, 34, 4043–4048; (c) 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, 9285–9289; (d) Chen, J.-R.; Lu,
H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J. Org.
Lett. 2005, 7, 4543–4545; (e) Singh Chimni, S.; Mahajan,
D.; Suresh Babu, V. V. Tetrahedron Lett. 2005, 46, 5617–
5619; (f) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G.
Org. Lett. 2005, 7, 5321–5323; (g) He, L.; Tang, Z.; Cun,
L.-F.; Mi, A. Q.; Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron
2006, 62, 346–351; (h) Cheng, C.-L.; Sun, J.; Wang, C.;
Scheme 1. Direct aldol reaction of 4-nitrobenzaldehyde and cyclo-
pentanone catalyzed by catalysts 2 and 5.

7796
J.-F. Zheng et al. / Tetrahedron Letters 47 (2006) 7793–7796
Zhang, Y.; Wei, S.-Y.; Jiang, F.; Wu, Y.-D. Chem.
Commun. 2006, 215–217.
9. (a) Jiang, M.; Zhu, S.-F.; Yang, Y.; Gong, L.-Z.; Zhou,
(f) Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron
Lett. 2005, 46, 8185–8187; (g) Andreae, M. R. M.; Davis,
A. P. Tetrahedron: Asymmetry 2005, 16, 2487–2492; (h)
Tsogoeva, S. B.; Wei, S.-W. Tetrahedron: Asymmetry
2005, 16, 1947–1951.
X.-G.; Zhou, Q.-L. Tetrahedron: Asymmetry 2006, 17,
´
384–387; (b) Guillen, G.; Hit, M. C.; Najer, C. Tetra-
hedron: Asymmetry 2006, 17, 729–733; (c) Gryko, D.;
Kowalczyk, B.; Zawadzki, Ł. Synlett 2006, 1059–1062.
12. (a) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal.
2004, 346, 1141–1146; (b) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Ley, S. V. Org. Biomol. Chem. 2005,
3, 84–96.
´
10. Gryko, D.; Lipinski, R. Adv. Synth. Catal. 2005, 347,
1948–1952.
11. (a) Tang, Z.; Yang, Z.-H.; Cun, L.-F.; Gong, L.-Z.; Mi,
A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285–2287; (b)
Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wenne-
mers, H. Org. Lett. 2005, 7, 1101–1103; (c) Kofoed, J.;
Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett.
2003, 13, 2445–2447; (d) Martin, H. J.; List, B. Synlett
2003, 1901–1902; (e) Shi, L.-X.; Sun, Q.; Ge, Z.-M.; Zhu,
Y.-Q.; Cheng, T.-M.; Li, R.-T. Synlett 2004, 2215–2217;
13. Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002,
58, 8167–8177.
14. McManus, H. A.; Barry, S. M.; Andersson, P. G.
Tetrahedron 2004, 60, 3405–3416.
´
15. Codova, A.; Zou, W.-B.; Ibrahem, I. Chem. Commun.
2005, 28, 3586–3588.
16. Cescon, L. A.; Day, A. R. J. Org. Chem. 1962, 27, 581–
586.