Small peptides catalyze highly enantioselective direct aldol reactions of aldehydes with hydroxyacetone: Unprecedented regiocontrol in aqueous media

Article abstract of DOI:10.1021/ol049141m

L-Proline-based small peptides have been developed as efficient catalysts for the asymmetric direct aldol reactions of hydroxyacetone with aldehydes. Chiral 1,4-diols 7, which are disfavored products in similar aldol reactions catalyzed by either aldolases or t-proline, were obtained in high yields and enantioselectivities of up to 96% ee with peptides 3 and 4 in aqueous media.

Full text of DOI:10.1021/ol049141m

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2285-2287
Small Peptides Catalyze Highly
Enantioselective Direct Aldol Reactions
of Aldehydes with Hydroxyacetone:
Unprecedented Regiocontrol in Aqueous
Media
Zhuo Tang, Zhi-Hua Yang,† Lin-Feng Cun, Liu-Zhu Gong,* Ai-Qiao Mi, and
Yao-Zhong Jiang
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan ProVince
and Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, and
Graduate School of Chinese Academy of Sciences, Beijing, China
gonglz@cioc.ac.cn
Received May 11, 2004
ABSTRACT
L-Proline-based small peptides have been developed as efficient catalysts for the asymmetric direct aldol reactions of hydroxyacetone with
aldehydes. Chiral 1,4-diols 7, which are disfavored products in similar aldol reactions catalyzed by either aldolases or L-proline, were obtained
in high yields and enantioselectivities of up to 96% ee with peptides 3 and 4 in aqueous media.
The aldol reaction is one of the most powerful methods for
forming carbon-carbon bonds. The great synthetic useful-
ness of the aldol reaction in organic synthesis has driven a
rapid development of numerous highly enantioselective chiral
catalysts.1,2 Direct aldolization is atom economic,3 and thus
it is an attractive method for the synthesis of polyoxygenated
compounds. Several catalysts, including aldolase,2e,4 transi-
tion metal complexes,5,6 and organic molecules,7,8 have been
reported for the direct asymmetric aldol reaction. Some of
(4) For examples, see: (a) Barbas, C. F., III; Heine, A.; Zhong, G.;
Hoffmann, T.; Gramatikova, S.; Bjo¨rnestedt, R.; List, B.; Anderson, J.; Stura,
E. A.; Wilson, I. A.; Lerner, R. Science 1997, 278, 2085. (b) Hoffmann,
T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner,
R.; Barbas, C. F., III. J. Am. Chem. Soc. 1998, 120, 2768. (c) List, B.;
Shabat, D.; Barbas, C. F., III; Lerner, R. Chem. Eur. J. 1998, 4, 881.
(5) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yoshikawa, N.; Yamada,
Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121,
4168. (c) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima,
T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466.
(6) (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (b)
Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367.
† Visiting Scholar from Sichuan University.
(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, Chapter 1.7.
(2) For reviews, see: (a) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem.
Eur. J. 1998, 4, 1137. (b) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9,
357. (c) Carreira, E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999;
Vol. III, Chapter 29.1. (d) Mahrwald, R. Chem. ReV. 1999, 99, 1095. (e)
Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352.
(3) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259.
10.1021/ol049141m CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/03/2004

them can also catalyze aldol reactions of hydroxyacetone to
exclusively give 1,2-diols with excellent regio- and enantio-
selectivity.4,8c In sharp contrast, an efficient catalyst for the
asymmetric direct aldol reactions of aldehydes with hydroxy-
acetone at its methyl group to give chiral 1,4-diols has not
yet reported, and thus it is much more difficult to directly
access optically active 1,4-diols than 1,2-diols by aldolization.
noncovalent bonding environment similar to that of an
enzyme, which is beneficial for stereocontrol, may be created
with an increase in the size of peptides.11 We report here
that L-proline-based peptides 1-5 can catalyze the aldol
reactions of hydroxyacetone with aldehydes 6 in aqueous
media12 to give 1,4-diols 7, the disfavored products, with
either aldolase or L-proline4,8c with high regio- and enantio-
selectivity.
First, we used 20 mol % Pro-Thr-OMe (1a), which
catalyzed the aldol reaction of acetone with 4-nitrobenz-
aldehyde in 67% ee,8f,9 to promote the aldol addition of
4-nitrobenzaldehyde (6a) with hydroxyacetone in THF to
give the normal anti-1,2-diol (8a) with 2.1: 1 dr and 61%
ee. The minor product 1,4-diol (7a) was also isolated in 16%
yield and 60% ee (Table 1, entry 1). A survey of different
Table 1. Direct Aldol Reaction of 4-Nitrobenzaldehyde with
Hydroxyacetone Catalyzed by Peptides 1-5a
% yield
ee
% yield
%
b
entry catalyst
solvent
THF
DMF
MeOH
CHCl3
of 7a
(%)c of 8a (dr)d eee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
2b
2c
3
16
7
60
55
68
69
54
54
62
67
52
56
68
68
56
75
76
78
82f
87g
71 (2.1:1) 61
69 (2.8:1) 72
76 (1.7:1) 63
71 (0.8:1) 23
17 (0.9:1) 19
20 (0.8:1) 10
13 (0.8:1) 28
30 (0.9:1) 37
38 (0.9:1) 16
35 (1.0:1) 25
30 (1.1:1) 33
30 (1.1:1) 32
30 (0.7:1) 22
30 (1.3:1) 35
35 (2.0:1) 41
58 (1.1:1) 29
18 (1.7:1) 47
21 (1.6:1) 30
Figure 1. Peptides evaluated in this study.
19
13
35
20
50
70
52
65
70
70
62
70
57
39
82
76
Very recently, we8f,9 and other groups10 found that L-
proline amides and dipeptides acted as efficient catalysts for
the asymmetric direct aldol reaction. Synthetic peptides have
proven to be promising organic catalysts for some important
transformations and continue to receive growing interest.11
On the basis of these observations, we reasoned that larger
L-proline-based peptides might be useful as organic catalysts
for direct aldol addition, since they are structurally similar
to L-proline amides but contain more amide units, which are
the same building blocks that constitute enzymes. A chiral
DMF/H2O
MeOH/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
4
5
3
4
(7) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615.
a Unless specified otherwise, the concentration of aldehyde is 0.25 M,
and v/v of hydroxyacetone/solvent is 1/4 (1/5 vol hydroxyacetone). b Organic
solvent/H2O ) 1:1. c Ee values were determined by HPLC, and the
configuration was assigned as R by comparison of the optical rotation with
value in the literature.15 d Anti:syn ratio was determined by HPLC. e Ee
value of anti isomer, determined by HPLC. f Reaction temperature ) 0 °C;
v/v of hydroxyacetone/solvent ) 1/2 (1/3 vol hydroxyacetone); reaction
time ) 4 days. g Performed with 10 mol % catalyst 4; reaction temperature
) 0 °C; v/v of hydroxyacetone/solvent ) 1/2 (1/3 vol hydroxyacetone);
reaction time ) 6 days.
(8) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260. (c) Notz, W.; List, B. J. Am. Chem. Soc. 2000,
122, 7386. (d) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. (e) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2002,
124, 3220. (f) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi,
A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. For
reviews, see: (g) List, B. Tetrahedron 2002, 58, 5573. (h) List, B. Synlett
2001, 1675.
(9) 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.
(10) (a) Martin, H. J.; List, B. Synlett 2003, 1901. (b) Kofoed, J.; Nielsen,
J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445.
(11) For examples, see: (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N.
D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910. (b) Sigman, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901 (c) Miller, S. J.;
Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am.
Chem. Soc. 1998, 120, 1629. (d) Sculimbrene, B. R.; Miller, S. J. J. Am.
Chem. Soc. 2001, 123, 10125. (e) Guerin, D. J.; Miller, S. J. J. Am. Chem.
Soc. 2002, 124, 2134. (f) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J.
J. Am. Chem. Soc. 2002, 124, 11653. For a review, see: (g) Jarvo, E. R.;
Miller, S. J. Tetrahedron 2002, 58, 2481.
solvents such as DMF, methanol, and chloroform revealed
that more polar solvents give better enantioselectivity of 1,2-
diol 8a than less polar solvents (entries 1-4). In DMF, anti-
1,2-diol was obtained with 2.8:1 dr and 72% ee (entry 2). In
a protic solvent, for example, MeOH, 1,4-diol was generated
in 19% yield (entry 3), which was a greater yield than in
nonprotic solvents (entries 1, 2, and 4). Surprisingly, the aldol
2286
Org. Lett., Vol. 6, No. 13, 2004

reaction preferentially occurred at the methyl group of
hydroxyacetone to give mostly 1,4-diol 7a when the same
reaction was conducted in the presence of catalyst 1a in an
aqueous media (entries 5-7). These are unprecedented
results compared to those observed in similar reactions
catalyzed by aldolase4 and L-proline.8c Antibody 84G3
preferentially catalyzed the aldolization of methoxylacetone
at the methyl group.13 Direct aldol reactions of siloxy and
alkoxy acetones with aldehydes mediated by TiCl4/Bu3N or
Bu2BOTf also took place regioselectively at the methyl
group, probably due to favorable formation of the less
hindered enamine.14 However, the hydroxyacetone was not
tested as a donor in these cases.13,14 In a 1:1 THF/H2O solvent
mixture, 1,4-diol 7a was obtained in 50% yield and 62%
ee, whereas 1,2-diol was obtained in only 13% yield (entry
7). An examination of the ability of various dipeptides 1b-d
to catalyze the model reaction indicated that peptides with
phenylalanine as a lipophilic residue gave better results and
Pro-Phe-OMe (1b) was more promising for this reaction in
terms of both yields and enantioselectivities (entries 8-10).
Tripeptides 2a and 2b gave similar yields and enantio-
selectvities (entries 11 and 12), but 2c resulted in a much
lower stereo-outcome (entry 13). A further increase in the
peptide size led to a significant increase in enantioselectivity,
but the regioselection to generate 1,4-diol was gradually
sacrificed (entries 14-16). These results demonstrated that
the peptide size also played an important role in the stereo-
and regiocontrol besides the solvent effect. The yields
increased by increasing the amount of hydroxyacetone from
1/5 to 1/3 reaction volume, and the enantioselectivity was
enhanced by conducting reactions at 0 °C (entries 17 and
18). As little as 10 mol % 4 is sufficient to catalyze the aldol
reaction, with 76% yield and 87% ee, under optimal
conditions (entry 18). However, L-proline did not catalyze
the reaction, and simple L-prolinamides gave worse results
than peptides 3 or 4 under the optimal conditions (Table S1
in Supporting Information).
Table 2. Direct Aldol Reactions of Acetone with Aldehydes
by Chiral Organic Catalyst 3a or 4b
entry
product (R)
catalyst
yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-NO2C6H4 (7a )
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
82
76
88
70
82
66
82
80
68
59
78
56
83
71
84
73
82
87
84
84
86
88
85
89
91
92e
85
86
91
93
96
96
4-CNC6H4 (7b)
4-CF3C6H4 (7c)
3-NO2C6H4 (7d )
3,5-Br2C6H4 (7e)
2-ClC6H4 (7f)
2-NO2C6H4 (7g)
2,6-Cl2C6H4 (7h )
a Reaction time ) 4 days, in the presence of 20 mol % 3. b Reaction
time ) 6 days, in the presence of 10 mol % 4. c Isolated yields based on
aldehydes. d Determined by HPLC. e THF/H2O ) 2:1
catalytic activity relies on the electron density of the aromatic
substituents of aldehydes. In general, peptide 4 gave a slightly
greater enantioselectivity than 3, but with lower yields, and
required a longer reaction time for complete conversion.
In conclusion, we have developed small peptides as
efficient catalysts for the asymmetric direct aldol reactions
of hydroxyacetone with aldehydes. Chiral 1,4-diols 7, which
are disfavored products in similar aldol reactions catalyzed
by either aldolases or L-proline,4,8c were obtained in high
yields and enantioselectivities with peptides 3 and 4 in
aqueous media. To our knowledge, this reaction is a unique
method for preparing the chiral 1,4-dihydroxyl-2-ones 7
directly from aldehydes and 2-hydroxyl ketones. Active
studies on mechanistic aspects and the application of these
catalysts to the synthesis of biologically active compounds
are underway.
The abilities of peptides 3 and 4 to catalyze the direct aldol
reactions of hydroxyacetone with a variety of aldehydes were
examined under optimal conditions. The results are shown
in Table 2. High yields and entioselectivities of up to 96%
ee were observed for aromatic aldehydes bearing electron-
withdrawing groups (7a-h, entries 1-16). In contrast,
neither 3 nor 4 catalyzed the aldol reactions of benzaldehyde
and aromatic aldehydes with electron-donating groups under
the optimal conditions, and the aldol reaction with an
aliphatic aldehyde such as cyclohexanaldehyde did not
proceed in the presence of either 3 or 4.16 Thus, the present
peptide catalyst seems to be substrate-specific, and its
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(Projects 203900505 and 20325211).
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) For Mukaiyama aldol reactions in aqueous media, see: (a) Na-
gayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 11531. (b) Hamada,
T.; Manbe, K.; Ishikawa, S.; Nagayama, S.; Shiro, M.; Kobayashi, S. J.
Am. Chem. Soc. 2003, 125, 2989. For a direct aldol reaction, see ref 8e.
(13) Maggiotti, V.; Resmini, M.; Gouverneur, V. Angew. Chem., Int.
Ed. 2002, 41, 1012.
OL049141M
(14) (a) Yoshida, Y.; Matsumoto, N.; Hamasaki, R.; Tanabe, Y.
Tetrahedron Lett. 1999, 40, 4227. (b) Tanabe, Y.; Matsumoto, N.; Higashi,
T.; Misaki, T.; Itoh, T. Yamamoto, M.; Mitarai, K.; Nishii, Y. Tetrahedron
2002, 58, 8269. (c) Samadi, M.; Munoz-Letelier, C.; Poigny, S.; Guyot,
M. Tetrahedron Lett. 2000, 41, 3349.
(15) Maggiotti, V.; Wong, J.-B.; Razet, R.; Cowley, A. R.; Gouverneur,
V. Tetrahedron: Asymmetry 2002, 13, 1789.
(16) No conversion was observed with aldol reactions of C6H5CHO (7i),
4-MeC6H4CHO (7j), and c-C6H11CHO (7k).
Org. Lett., Vol. 6, No. 13, 2004
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