Dry and wet prolines for asymmetric organic solvent-free aldehyde-aldehyde and aldehyde-ketone aldol reactions

Article abstract of DOI:10.1039/b613262f

Dry and wet prolines were found to catalyze the direct aldol reactions of aldehyde-aldehyde and aldehyde-ketone, respectively, to afford aldols with excellent diastereo- and enantioselectivities, and an organic solvent-free reaction was realized in some c

Full text of DOI:10.1039/b613262f

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Dry and wet prolines for asymmetric organic solvent-free aldehyde–
aldehyde and aldehyde–ketone aldol reactions{
Yujiro Hayashi,* Seiji Aratake, Takahiko Itoh, Tsubasa Okano, Tatsunobu Sumiya and Mitsuru Shoji
Received (in Cambridge, UK) 12th September 2006, Accepted 27th November 2006
First published as an Advance Article on the web 8th December 2006
DOI: 10.1039/b613262f
tryptophan-catalyzed reaction in the presence of water.12 During
Dry and wet prolines were found to catalyze the direct aldol
our further investigation of aldol reaction in the presence of water,
we happened to find that a highly enantioselective aldol reaction
can proceed under either dry or under wet conditions without
organic solvent, as we describe below.
reactions of aldehyde–aldehyde and aldehyde–ketone, respec-
tively, to afford aldols with excellent diastereo- and enantio-
selectivities, and an organic solvent-free reaction was realized in
some cases.
It has generally been believed that proline does not catalyze the
aldol reaction in the presence of water, or that even when the
reaction does proceed, as in the presence of surfactant, a nearly
racemic aldol product is obtained.13 In fact, using the conditions
under which we had previously investigated the self-aldol reaction
of propanal,14 or the aldol reaction of o-chlorobenzaldehyde and
propanal,10 catalyzed by proline in the presence of water no
reaction was observed. However, when we examined the aldol
reaction of o-chlorobenzaldehyde and propanal with higher
catalyst loading and at higher temperature, we found that the
proline-mediated aldol reaction proceeded slowly in the presence of
water to afford the product enantioselectively. Even in the presence
of a large excess (100 equiv.) of water, moderate yield and
enantioselectivity were obtained (Table 1, entry 1). These results
indicate that propanal can react with a reactive electrophilic
aldehyde even in the presence of a large excess of water. In the
present reaction, a two-phase system is formed, and the reaction is
thought to proceed according to eqn. (1):
Today ‘‘Green’’ is an increasingly important keyword and the
development of green reactions is one of the most urgent and
important topics in current chemistry.1 The synthesis of enantio-
pure molecules is another important issue,2 and the development
of enantioselective reactions that proceed under environmentally
benign conditions has grown into an extensively investigated field.
Successful catalytic, enantioselective reactions have mostly used
transition metal complexes, and hence may require toxic, rare and
expensive metals and so suffer from possible metal contamination
of the products, while most also require an organic solvent.
Asymmetric catalytic reactions that proceed with a benign catalyst
and without using an organic solvent would be highly desirable.3
Proline is free from the problems associated with some metals, as it
is safe, inexpensive, and stable to moisture and air.4 Thus, the
development of proline-mediated enantioselective reactions not
requiring an organic solvent has become a highly sought-after goal
in green chemistry.
The aldol condensation is a key carbon–carbon bond forming
reaction creating the b-hydroxy carbonyl structural unit found in
many natural products and drugs.5 Several excellent asymmetric
aldol reactions have been developed, and it is known that proline
catalyzes such reactions in polar organic solvents such as DMSO
and DMF,6 a reaction that has been reported not to proceed in
water.7,8 Pihko et al. reported the highly enantioselective aldol
reaction in aqueous DMF, in which the reaction proceeds
efficiently in the presence of a large excess of water.8c,l It had
been thought that modification of proline is required to achieve
such aldol reactions in the presence of water without organic
solvent, and recently we developed a highly lipophilic siloxyproline
catalyst9 and a combined proline–surfactant organocatalyst10 to
make possible aldehyde–ketone and aldehyde–aldehyde aldol
reactions in the presence of water, respectively. Barbas and
co-workers11 have reported the combined use of a diamine and an
acid to achieve aldol reaction in the presence of water. During the
preparation of this manuscript, Lu and co-workers have reported a
ð1Þ
o-Chlorobenzaldehyde and some portion of the propanal form an
organic phase. The remaining propanal dissolves in the aqueous
phase, where it reacts with proline, most of which stays in the
water in its zwitterionic form 1, to generate neutral N,O-acetal 2,
which moves into the organic phase. Enamine 3 can be regenerated
from 2 and react with o-chlorobenzaldehyde to generate the aldol
product in the organic phase. Some water is dissolved in the
organic phase, stabilizing 3 and reducing its reactivity, which is
why 3 reacts with electron-deficient o-chlorobenzaldehyde but not
with propanal. As propanal dissolves in both the aqueous and
organic phases, in effect it extracts proline from water to the
organic phase.
In order to improve the yield and enantioselectivity, the effect
of amount of water on diastereo- and enantio-selectivities was
investigated in detail. Reducing the amount of water increases
both the yield and enantioselectivity. However with no water, the
yield was reduced owing to over-reactions such as dehydration
(entry 8). This side-reaction under neat conditions can be
Department of Industrial Chemistry, Faculty of Engineering, Tokyo
University of Science, Kagurazaka, Shinjuku-ku, Tokyo, 162-8601,
Japan. E-mail: hayashi@ci.kagu.tus.ac.jp; Fax: +81-(0)3-5261-4631;
Tel: +81-(0)3-5228-8318
{ Electronic supplementary information (ESI) available: Detailed experi-
mental procedures, full characterization, 1H, 13C NMR and IR spectra of
all new compounds. See DOI: 10.1039/b613262f
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Chem. Commun., 2007, 957–959 | 957

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Table 1 The effect of amount of water on the yield, and diastereo-
and enantio-selectivities in the aldol reaction of o-chlorobenzaldehyde
and propanala
Table 2 The effect of amount of water on the yield, and diastereo-
and enantio-selectivities in the aldol reaction of o-chlorobenzaldehyde
and cyclohexanonea
Amount of
water (equiv.)
Amount Amount
of water of proline
Entry (equiv.) (mol%)
Entry
Yieldb (%)
anti : sync
Eed (%)
Yieldb anti : Eed
Temp./uC Time/h (%) (%)
sync
1
2
3
4e
5
6
a
0
1
3
3
5
18
75
70
71
70
51
11
3.0 : 1
9.5 : 1
13.9 : 1
12.5 : 1
12.2 : 1
7.3 : 1
84
96
98
97
97
95
1
2
3
4
5
6
7
8
100
54
36
18
10
5
3
0
0
0
30
30
30
30
30
30
30
30
30
10
10
10
10
10
23
23
23
23
23
23
23
23
4
4
4
0
4
72
72
72
72
72
72
72
72
48
48
60
24
48
48
39
60
65
73
71
70
62
54
85
90
76
,5
79
78
2.4 : 1 67
3.5 : 1 77
3.0 : 1 82
3.9 : 1 88
3.9 : 1 89
4.3 : 1 90
5.6 : 1 92
4.4 : 1 86
7.1 : 1 96
13 : 1 96
9.7 : 1 96
Unless otherwise shown, the reaction was conducted with 0.4 mmol
of o-chlorobenzaldehyde, 2 mmol of cyclohexanone and 0.12 mmol
of proline at room temperature for 72 h.
b
Isolated yield.
Determined by 1H NMR. Ee of anti-isomer. Determined by
chiral HPLC (see ESI). 3.0 equiv. of cyclohexanone was employed.
c
d
9
e
10
11e
12f
13g
14h
a
0
18
0
12 : 1 98
19 : 1 98
(60 wt% solution in water) can be used directly under wet
conditions, and reacts with 3-phenylpropanal affording the aldol
with excellent enantioselectivity. As for the aldehyde–ketone
reaction, aqueous dimethoxyacetaldehyde reacts with cyclohexa-
none and cyclopentanone to provide b-hydroxyketones with
excellent enantioselectivity. It should be noted that its reaction
with 2,2-dimethyl-1,3-dioxan-5-one affords a polyfunctionalized
ketone in excellent enantioselectivity, a useful intermediate for the
synthesis of sugars.15 Though cyclohexanone scarcely reacts with
benzaldehyde, it reacts efficiently with reactive, electron-deficient
aromatic aldehydes such as o-chloro-, p-nitro- and p-trifluoro-
methyl-benzaldehydes with excellent enantioselectivity.
0
4
Unless otherwise shown, the reaction was conducted with 0.4 mmol
b
of o-chlorobenzaldehyde and 2 mmol of propanal. Isolated yield.
c
d
Determined by 1H NMR. Ee of anti-isomer. Determined by
chiral HPLC after conversion to the monobenzoyl ester (see ESI).
e
f
g
3.0 equiv. of propanal was employed. The data in ref 10. 4-tert-
Butyldiphenylsiloxyproline was employed instead of proline.
4-Decanoyloxyproline was employed instead of proline.
h
suppressed by performing the reaction at the lower temperature
of 4 uC, when the product is formed in good yield and with
higher diastereo- and enantio-selectivities (entry 9). The amount
of aldehyde and catalyst can be reduced to 3 equiv. and
10 mol%, respectively, with only a slight decrease in yield, and
without compromising the enantioselectivity (entries 10, 11). When
4-tert-butyldiphenylsiloxyproline9 or 4-decanoyloxyproline10 was
employed instead of proline, good yield and excellent enantio-
selectivity was obtained (entries 13, 14).
Organic solvent is usually necessary not only during the reaction
but also at the extraction and purification stages. A noteworthy
advantage of the present reaction is the realization of an organic
solvent-free system. As proline is soluble in water, it was easily
removed and recovered from other organic materials by simply
washing the organic phase with water. Direct distillation of the
remaining organic phase afforded the pure aldols without
compromising the enantioselectivity. By this procedure 11.7 g
(75%) of the aldol product of cyclopentanone and o-chloroben-
zaldehyde was obtained in .99% ee (anti : syn = 2 : 1) without
using any organic solvent (for detailed procedure see ESI{).
When the aldols were crystalline, direct recrystallization of the
organic phase after washing with water gave diastereomerically
and enantiomerically pure aldols. By this procedure 11.4 g (73%)
of the aldol adduct of p-trifluoromethylbenzaldehyde and cyclo-
hexanone was obtained in .99% ee (anti : syn = .20 : 1), using
57.6 mL of cyclohexane as recrystallization solvent (for detailed
procedure see ESI{).
As the best conditions for the cross-aldol reaction of aldehydes
had been established as neat at 4 uC, these were applied to
aldehyde–ketone aldol reaction, for which the reaction of
o-chlorobenzaldehyde and cyclohexanone was selected as a model
(Table 2). In this case, a small amount of water has a beneficial
effect on both diastereo- and enantio-selectivities. Though the
reaction proceeds without solvents, the diastereomer ratio (dr) is
low (3.0 : 1) and ee is moderate (84% ee). In the presence of
3 equiv. of water, dr and ee are increased to 13.9 : 1 and 98% ee,
respectively. Wet proline is suitable and the reaction scarcely
proceeded in the presence of an excess amount of water. The same
positive effect of water has been observed in some cases,8,9 but the
reason of its effect is not clear at this moment.
Proline, which may have been present in the prebiotic era,16
promotes the aldehyde–aldehyde aldol reaction in a presence of a
large excess of water, affording the product in good enantioselec-
tivity (Table 1, entry 1). This is a first example, in which an amino
acid can promote the aldol reaction with high enantioselectivity in
a presence of a large excess amount of water without organic
solvent. This result may be evidence that proline could have
promoted enantioselective aldol reactions in the presence of water
and so created enantiomerically-enriched on the early Earth.17
The generality of the reactions under dry conditions for the
aldehyde–aldehyde reaction and wet conditions for the aldehyde–
ketone reaction was investigated with the results summarized in
Table 3. Propanal reacts with reactive o-chlorobenzaldehyde and
p-trifluoromethylbenzaldehyde enantioselectively under dry condi-
tions. Not only electron-deficient aromatic aldehydes, but also
benzaldehyde itself can be employed, though the yield is moderate.
The heteroaromatic aldehyde 2-furaldehyde is also a suitable
substrate. The water-soluble aldehyde dimethoxyacetaldehyde
958 | Chem. Commun., 2007, 957–959
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3 Solvent-free asymmetric catalytic reactions, see: (a) M. Tokunaga,
J. F. Larrow, F. Kakiuchi and E. N. Jacobsen, Science, 1997, 277, 936;
(b) A. G. Dossetter, T. F. Jamison and E. N. Jacobsen, Angew. Chem.,
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J. Am. Chem. Soc., 2002, 124, 10; (d) F. Shibahara, K. Nozaki and
T. Hiyama, J. Am. Chem. Soc., 2003, 125, 8555; (e) S.-J. Jeon, H. Li and
P. J. Walsh, J. Am. Chem. Soc., 2005, 127, 16416; reviews, see: (f)
J. O. Metzger, Angew. Chem., Int. Ed., 1998, 21, 2975; (g) K. Tanaka,
Solvent-free Organic Synthesis, Wiley-VCH, Weinheim, 2003.
4 (a) A. Berkssel and H. Groger, Asymmetric Organocatalysis, Wiley-
VCH, Weinheim, 2005; (b) P. I. Dalko and L. Moisan, Angew. Chem.,
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63, 464.
Table 3 Enantioselective direct, proline-mediated aldol reactiona
5 Modern Aldol Reactions ed. R. Mahrwald, Wiley-VCH, Weinheim,
2004, vol. 1 and 2.
6 For representative papers, see: (a) Z. G. Hajos and D. R. Parrish, J. Org.
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Chem., Int. Ed. Engl., 1971, 10, 496; (c) B. List, R. Lerner and
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and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124, 6798; review,
see: (e) B. List, Modern Aldol Reactions, Wiley-VCH, Weinheim, 2004,
pp. 161–200.
7 Reviews as for the reactions in water, see: (a) Organic Synthesis
in Water, ed. P. A. Grieco, Blackie A & P, London, 1998; (b)
U. M. Lindstrom, Chem. Rev., 2002, 102, 2751; (c) C.-J. Li, Chem. Rev.,
2005, 105, 3095.
8 Organocatalysis-mediated asymmetric aldol reaction in aqueous solvent,
see: (a) T. J. Dickerson and K. D. Janda, J. Am. Chem. Soc., 2002, 124,
3220; (b) H. Torii, M. Nakadai, K. Ishihara, S. Saito and H. Yamamoto,
Angew. Chem., Int. Ed., 2004, 43, 1983; (c) A. I. Nyberg, A. Usano and
P. M. Pihko, Synlett, 2004, 1891; (d) Z. Tang, Z.-H. Yang, L.-F. Cun,
L.-Z. Gong, A.-Q. Mi and Y.-Z. Jiang, Org. Lett., 2004, 6, 2285; (e)
J. Casas, H. Sunden and A. Cordova, Tetrahedron Lett., 2004, 45, 6117;
(f) D. E. Ward and V. Jheengut, Tetrahedron Lett., 2004, 45, 8347; (g)
I. Ibrahem and A. Cordova, Tetrahedron Lett., 2005, 46, 3363; (h)
S. S. Chimni, D. Mahajan and V. V. S. Babu, Tetrahedron Lett., 2005,
46, 5617; (i) M. Amedjkouh, Tetrahedron: Asymmetry, 2005, 16, 1411;
(j) A. Cordova, W. Zou, I. Ibrahem, E. Reyes, M. Engqvist and
W.-W. Liao, Chem. Commun., 2005, 3586; (k) P. Dziedzic, W. Zou,
J. Hafren and A. Cordova, Org. Biomol. Chem., 2006, 4, 38; (l)
P. M. Pihko, K. M. Laurikainen, A. Usano, A. I. Nyberg and
J. A. Kaavi, Tetrahedron, 2006, 62, 317.
a
Yields are for isolated compounds, and diastereomer ratios were
determined by 1H NMR. Ee refers to that of the anti-isomer, and
were determined by chiral HPLC (see ESI). Condition A: acceptor
aldehyde : donor aldehyde : proline = 1 : 5 : 0.1. The reaction was
performed under neat conditions at 4 uC. The aldol product was
reduced with NaBH4 and isolated as a diol. Conditions B: acceptor
aldehyde : carbonyl compound : proline = 1 : 5 : 0.3. Commercially
available aqueous aldehyde was employed as received (3.8 equiv. of
water), and the reaction was performed at room temperature.
Conditions C: aldehyde : ketone : proline = 1 : 3 : 0.3. The reaction
was performed in the presence of 3 equiv. amount of water at room
temperature. bThe aldol product was reduced with NaBH4 and
isolated as a diol.
9 Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima and
M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 958.
10 Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya and
M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 5527.
11 N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and
C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 734.
12 Z. Jiang, Z. Liang, X. Wu and Y. Lu, Chem. Commun., 2006,
2801.
13 A. Cordova, W. Notz and C. F. Barbas, III, Chem. Commun., 2002,
3024.
14 S. Aratake, T. Itoh, T. Okano, T. Usui, M. Shoji and Y. Hayashi,
manuscript in preparation.
15 (a) D. Enders and C. Grondal, Angew. Chem., Int. Ed., 2005, 44, 1210;
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and E. Reyes, Chem. Eur. J., 2005, 11, 4772; (d) D. Enders, J. Palecek
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D. Enders, Tetrahedron, 2006, 62, 329; (f) I. Ibrahem and A. Cordova,
Tetrahedron Lett., 2005, 46, 3363; (g) review of the proline-catalyzed
carbohydrate synthesis, see: D. Enders, M. Voith and A. Lenzen,
Angew. Chem., Int. Ed., 2005, 44, 1304.
In summary, we have found practical enantioselective aldehyde–
aldehyde and aldehyde–ketone aldol reactions catalyzed by the
inexpensive and safe catalyst proline under dry and wet conditions.
There are several noteworthy synthetic advantages to the present
reaction. (1) Any modification of proline is not required, and the
proline catalyst can be used as it stands. (2) Commercially
available aqueous aldehydes such as dimethoxyacetaldehyde can
be employed directly. (3) In some cases a completely organic
solvent-free procedure can be achieved. As operation is simple and
scale-up is easy, the present method is suitable for the large-scale
preparation of chiral aldols.
16 G. M. M. Caro, U. J. Meierhenrich, W. A. Schutte, B. Barbier,
A. A. Segovia, H. Rosenbauer, W. H.-P. Thiemann, A. Brack and
J. M. Greenberg, Nature, 2002, 416, 403.
17 J. T. Suri, S. Mitsumori, K. Albertshofer, F. Tanaka and C. F. Barbas,
III, J. Org. Chem., 2006, 71, 3822, and references therein.
Notes and references
1 R. Noyori, Chem. Commun., 2005, 1807.
2 Comprehensive Asymmetric Catalysis I–III, ed. E. N. Jacobsen, A. Pfaltz
and H. Yamamoto, Springer, Berlin, 1999.
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Chem. Commun., 2007, 957–959 | 959