Asymmetric aldol reactions catalyzed by tryptophan in water

Article abstract of DOI:10.1039/b606154k

Tryptophan was shown to be able to catalyze direct aldol reactions between various cyclic ketones and aromatic aldehydes in water with high enantioselectivity. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606154k

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Asymmetric aldol reactions catalyzed by tryptophan in water{
Zhaoqin Jiang,ab Zhian Liang,a Xiaoyu Wua and Yixin Lu*ab
Received (in Cambridge, UK) 2nd May 2006, Accepted 12th May 2006
First published as an Advance Article on the web 26th May 2006
DOI: 10.1039/b606154k
products with low or no enantioselectivity.11 Although it was
shown in List’s initial report8a that primary and acyclic secondary
Tryptophan was shown to be able to catalyze direct aldol
reactions between various cyclic ketones and aromatic alde-
amino acids failed to catalyze aldol reactions, Cordova and co-
workers elegantly demonstrated that acyclic amino acids could
effect the direct aldol reaction in DMSO with the addition of
water.12 We reasoned that a hydrophobic amino acid might be an
efficient aldol catalyst in aqueous media. It is hypothesized that a
hydrophobic catalyst should associate strongly with hydrophobic
reactants in water. As a result of optimizing hydrophobic
interactions, the transition state may be better defined and high
enantioselectivity might be achieved. Herein, we report our
preliminary finding that tryptophan is an efficient catalyst for
the direct aldol reaction in water.
hydes in water with high enantioselectivity.
The use of water as a solvent for chemical reactions is of great
current interest,1 mainly due to the low cost, safety and
environmentally benign nature of water. Ever since the seminal
contributions from Breslow and Grieco in the early 1980s on the
positive effects of water on the Diels–Alder reaction,2 water has
gained increasing recognition as a solvent for organic reactions.
In aqueous organic reactions, it is generally assumed that
homogeneous solution is essential for an efficient chemical
reaction. Therefore, a central theme of aqueous organic chemistry
is to promote solubility of reactants and reagents in these
reactions. However, some recent discoveries demonstrated that
homogeneity is not essential for organic reactions to occur in
aqueous media. Sharpless and co-workers reported several
examples showing that substantial rate acceleration could be
achieved in aqueous suspension, under what they denoted as ‘‘on
water’’ conditions.3 The groups of Takabe, Barbas and Hayashi
showed that the direct asymmetric aldol reactions could be carried
out with excellent enantioselectivity in water by employing proline-
derived organocatalysts.4 Although the high reactivity of such
inhomogeneous aqueous reactions is not fully understood, it is
quite clear that hydrophobic effects play a pivotal role in
promoting reactivity.5
In our initial screenings, we investigated the catalytic effects of a
number of natural amino acids in the direct aldol reactions
between cyclohexanone and p-nitrobenzaldehyde in water
(Table 1). Alanine was not very effective, and only low conversion
was achieved after about 4 days (entry 1). Increasing the size of the
amino acid side chain led to the improved catalytic effects. Valine,
leucine and isoleucine showed improved catalysis, although the
rates of the reactions were modest (entries 2–4). While tyrosine was
ineffective (entry 5), phenylalanine was a good catalyst, enabling
Table 1 Screening of organocatalysts for the asymmetric aldol
reactions of cyclohexanone and p-nitrobenzaldehyde in watera
The aldol reaction is one of the most important carbon–carbon
bond forming reactions,6 yielding the b-hydroxy carbonyl
structural scaffold which is frequently found in natural product
and medicinal agents. In nature, Class I aldolases catalyze highly
efficient and enantioselective aldol reactions in water via the
enamine mechanism. It is highly desirable to develop a chemical
system that can mimic the action of aldolase and effect direct aldol
reactions in water with excellent stereocontrol. Organocatalysis has
experienced a renaissance in recent years.7 There have been
numerous reports on direct, asymmetric aldol reactions catalyzed
by proline8 and its structural analogues7a,9 that utilize the enamine
mechanism. Proline is arguably the most efficient and versatile
small organic ‘‘enzyme’’ that catalyzes a wide range of organic
transformations.10 However, the proline-catalyzed aldol reactions
can only afford high enantioselectivity in organic solvents. The
presence of a large amount of water resulted in the formation of
Time Yieldb
eed
Entry Catalyst
(h)
(%)
anti:sync (%)
1
2
109
144
96
96
28
48
23
89
24
36
36
19
32
84
81
67
,5
75
85
57
82
82
85
91
12 : 1
4 : 1
3 : 1
5 : 1
—
0
L-Alanine
65
79
83
—
70
86
6
L-Valine
3
L-Leucine
4
L-Isoleucine
5
L-Tyrosine
6
4 : 1
4 : 1
1.3 : 1
1 : 1
4 : 1
5 : 1
5 : 1
L-Phenylalanine
L-Tryptophan
L-Tryptophan methylester
L-Tryptamine
L-Tryptophan
L-Tryptophan
L-Tryptophan
7
8
9
0
10e
11f
12g
a
74
92
96
aDepartment of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore 117543, Republic of Singapore.
E-mail: chmlyx@nus.edu.sg; Fax: +65-6779-1691; Tel: +65-6516-1569
bThe Medicinal Chemistry Program, Office of Life Sciences, National
University of Singapore, Republic of Singapore
The reactions were performed with p-nitrobenzaldehyde (0.5 mmol),
cyclohexanone (2.5 mmol) and catalyst (0.05 mmol) in water
b
c
(5 mmol) at room temperature. Isolated yield. Determined by 1H
NMR analysis of the products. ee of anti-isomer. 0.5 mmol of
d
e
f
g
cyclohexanone was used. 5.0 mol% catalyst was used. 10 mmol of
water was used.
{ Electronic supplementary information (ESI) available: experimental
details. See DOI: 10.1039/b606154k
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Chem. Commun., 2006, 2801–2803 | 2801

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Table 2 L-Tryptophan-catalyzed direct aldol reactions of various
substrates in watera
Table 2 L-Tryptophan-catalyzed direct aldol reactions of various
substrates in water (Continued)
a
Time Yieldc
eed
Time Yieldc
eed
anti:synb (%)
Entry Product
12
(h)
(%)
anti:synb (%)
Entry Product
1
(h)
(%)
24
77
52 : 1
20 : 1
6 : 1
90
89
88
20
94
1 : 1
81
2
3
4
5
24
24
96
42
79
78
66
42
a
The reactions were performed with aldehyde (0.5 mmol),
cyclohexanone (2.5 mmol) and tryptophan (0.05 mmol) in water
(5 mmol) at room temperature. Determined by 1H NMR analysis
of the products. Isolated yield. ee of anti-isomer. 5 mmol water
was used.
b
c
d
e
the completion of the reaction in 48 hours (entry 6). Tryptophan
was the best catalyst in our trials (entry 7). With 10 mol%
tryptophan, the desired aldol product was obtained in an 85%
yield with an 86% ee in less than one day.{ The tryptophan
carboxylic acid function seemed to be important for the
asymmetric induction, as the tryptophan methyl ester virtually
afforded a racemic product (entry 8). Tryptamine also catalyzed
the reaction (entry 9). The influence of the substrate ratio, catalyst
loading and the water quantity was next examined. Lowering the
amount of cyclohexanone resulted in a substantial decrease in the
product ee value (entry 10). If only 5 mol% tryptophan was used,
the reaction was completed after 36 hours with a slight increase in
ee (entry 11). The use of 20 equivalents of water with respect to the
aldehyde gave the best result, as the desired aldol product was
obtained in excellent yield and with excellent enantiomeric
selectivity (entry 12). In a typical aldol reaction that was catalyzed
by tryptophan, the reaction mixture was a two phase system where
tryptophan was suspended. It is clear that a homogeneous solution
is not essential for an efficient reaction to occur.
17 : 1
82
87
10 : 1
6
7
92
24
47
57
78 : 1
89
92
16 : 1
The scope of such tryptophan-catalyzed direct aldol reactions in
water was evaluated with a variety of cyclic ketones and aryl
aldehydes (Table 2). Generally, electron-poor aromatic aldehydes
are excellent substrates, with the reactions typically going to
completion within one day (entries 1 to 3). Less reactive aromatic
aldehydes (entries 4 to 7) and a heteroaromatic aldehyde (entry 8)
were also suitable—enantioselectivity remained very good, even
though longer reaction times were required. The ring size of the
cyclic ketones could be varied—both cyclopentanone and cyclo-
heptanone could serve as donors (entries 9 to 12). However, the
current method has its limitations, since we were unable to extend it
to include simple acyclic ketones and non-aromatic aldehydes. It
seems that the hydrophobic nature of the substrates is essential for
an efficient reaction to take place. For instance, the direct aldol
reaction between acetone and p-nitrobenzaldehye in water in the
presence of tryptophan did not yield any desired product.
8
72
12
49
74
5 : 1
85
78
9e
1 : 1
10
11
24
48
73
99
3 : 2
84
82
To understand the stereochemical outcome of our reactions, we
proposed that the tryptophan-catalyzed aldol reaction occurs via
the transition state13 as depicted in Fig. 1, whereby the enamine
attacks the aldehyde from the Re face, leading to the formation of
the major stereoisomer. We believe that the aromatic side chain of
1 : 4
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Fig. 1 Proposed transition state model.
tryptophan facilitates the formation of a hydrophobic core with
other hydrophobic substrates in water, thus promoting the aldol
reaction in aqua. The p–p stacking interaction may also be
involved in our reactions.
6 Modern Aldol Reactions, Vol. 1,2, ed. R. Mahrwald, Wiley-VCH,
Weinheim, 2004.
7 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138;
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9 For selective examples, see: (a) H. Torii, M. Nakadai, K. Ishihara,
S. Saito and H. Yamamoto, Angew. Chem., Int. Ed., 2004, 43, 1983; (b)
S. Saito and H. Yamamoto, Acc. Chem. Res., 2004, 101, 5755; (c)
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In summary, we demonstrated for the first time that a natural
hydrophobic amino acid with a primary amino function could be
directly used as an efficient aldol catalyst in aqueous media. The
described reactions are highly enantioselective, environmentally
benign and operationally simple. We believe that our finding will
open up a new avenue for the design of highly effective
organocatalysts in water. The further development of relevant
catalytic systems and the full extension of the scope of this
chemistry are in progress in our laboratory, and will be reported in
due course.
We thank the National University of Singapore for generous
financial support and Professor Peter W. Schiller for proofreading.
Notes and references
10 For reviews, see: (a) B. List, Synlett, 2001, 1675; (b) B. List, Acc. Chem.
Res., 2004, 37, 548; (c) W. Notz, F. Tanaka and C. F. Barbas, III, Acc.
Chem. Res., 2004, 37, 580.
11 (a) A. Cordova, W. Notz and C. F. Barbas, III, Chem. Commun., 2002,
3024; (b) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas, III, J. Am.
Chem. Soc., 2001, 123, 5260.
{ Typical Procedure for the L-tryptophan catalyzed aldol reaction in water:
L-Tryptophan (0.0102 g, 0.05 mmol) was added to a suspension of
p-nitrobenzaldehyde (0.0755 g, 0.5 mmol), cyclohexanone (0.25 ml,
2.5 mmol) and water (0.18 ml, 10 mmol) at room temperature. The
reaction mixture was stirred for 19 hours. The reaction mixture was
extracted with dichloromethane several times, and the combined organic
extracts were concentrated under the reduced pressure. Flash chromato-
graphy on silica gel (ethyl acetate : hexane 5 1 : 3) afforded 1 as a yellow
solid (0.1137 g, 91%).
12 A. Cordova, W. Zou, I. Ibrahem, E. Reyes, M. Engqvist and
W.-W. Liao, Chem. Commun., 2005, 3586.
13 (a) A. Bassan, W. Zou, E. Reyes, F. Himo and A. Cordova, Angew.
Chem., Int. Ed., 2005, 44, 7028. For some other selected examples of
catalytic reactions in partially aqueous systems, see: (b) C. E. Aroyan,
M. M. Vasbinder and S. J. Miller, Org. Lett., 2005, 7, 3849; (c) W. Zou,
I. Ibrahem, P. Dziedzic, H. Sunden and A. Cordova, Chem. Commun.,
2005, 4946; (d) Y. Xu and A. Cordova, Chem. Commun., 2006, 460.
1 (a) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751; (b) C.-J. Li, Chem.
Rev., 2005, 105, 2751; (c) Organic Synthesis in Water, ed. P. Grieco,
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2801–2803 | 2803