Small organic molecule in enantioselective, direct aldol reaction "in water"

Article abstract of DOI:10.1039/b702559a

A small organic molecule, Pro-NH₂, catalyzing the enantioselective aldol reaction "in water" not merely "in the presence of water" with good enantioselectivity has been discovered for the first time. The Royal Society of Chemistry.

Full text of DOI:10.1039/b702559a

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Small organic molecule in enantioselective, direct aldol reaction ‘‘in
water’’{
Seiji Aratake, Takahiko Itoh, Tsubasa Okano, Takahiro Usui, Mitsuru Shoji and Yujiro Hayashi*
Received (in Cambridge, UK) 19th February 2007, Accepted 5th March 2007
First published as an Advance Article on the web 20th March 2007
DOI: 10.1039/b702559a
proline–surfactant organocatalyst,12 both of which promote the
A small organic molecule, Pro–NH2, catalyzing the enantio-
asymmetric, direct aldol reaction with excellent enantioselectivity.
Though our reactions are efficient ‘‘in the presence of a large
amount of water’’,12,13 they proceed in the organic phase. Recently
we have reported the proline-mediated wet reaction.14 However
further searches for a small organic molecule, capable of
promoting the aldol reaction ‘‘in water’’ with high enantioselec-
tivity, have led us to proline amide, the first such molecule.
The self-aldol reaction of propanal was selected as the model
because it is a simple but fundamental aldol reaction important for
the biosynthesis of carbohydrates and terpenes, and because
propanal itself dissolves in water. The catalyst search was
performed in the presence of six equivalents of water, using
nineteen amino acids, of which Ala and Glu are non-racemic
amino acids characterized from the Murchison meteorite.15 The
reaction hardly proceeded at all in the presence of a catalytic
amount of most of these amino acids. The exceptions were Met,
Lys, and Arg which after 24 h afforded the products with low
enantioselectivity (,20% ee). Some dipeptides promoted the
reaction ‘‘in water’’. Ala-Ala, which was reported to promote
the aldol reaction of ketones and aldehydes in H2O–EtOH (1 : 1)
in an enantioselective manner,16 afforded the products with low
enantioselectivity. Good enantioselectivity was obtained for the
anti-isomer when Pro-Val was employed, while low ee was
obtained for the syn-isomer. On the other hand, amino amides
other than Glu–NH2 were found to promote the reaction in
reasonable yield. In the cases of Tyr–NH2, Phe–NH2 and Trp–
NH2, moderate enantioselectivity was obtained. Notable results
were obtained when Pro–NH2 was utilized: a moderate yield was
obtained in short time (3 h) with good enantioselectivities (syn:
74% ee, anti: 78% ee), in which the reaction mixture became cloudy
within 30 min.
selective aldol reaction ‘‘in water’’ not merely ‘‘in the presence
of water’’ with good enantioselectivity has been discovered for
the first time.
Reactions using water as a reaction medium are attracting a great
deal of attention,1 because water possesses unique properties,
including the ability to accelerate some organic reactions.2 Most of
organic reactions using water as a solvent are carried out ‘‘in the
presence of water’’, and the organic reagents and catalyst, when
one is used, are not actually dissolved in water, the reaction
proceeding in the organic phase. In particular, for the asymmetric
catalytic aldol reaction, which is a key carbon–carbon bond
forming reaction, creating b-hydroxy carbonyl compounds found
in many natural products and drugs,3 there is a controversy
whether they are really in ‘‘all wet’’.4,5 As far as we are aware there
is no example for which the reaction proceeds with high
enantioselectivity ‘‘in water’’, with all the reagents dissolved
homogeneously in water and the reaction proceeding in the
aqueous phase, catalyzed a small organic molecule. Thus, it has
been a great challenge to develop a small organic molecule,
promoting aldol reaction ‘‘in water’’ with suitable asymmetric
induction.4,5 Here we report such a small molecule for the first
time. We found that proline-amide, which may have been present
on the early Earth, promotes the aldol reaction ‘‘in water’’,
generating the aldol product with good enantioselectivity.
Over the past few years there have been a number of reports on
the asymmetric aldol reaction, a key process in organic synthesis,
in water. Metal-based Lewis acids have been reported to catalyze
the asymmetric Mukaiyama-type aldol reaction ‘‘in the presence of
water’’ in combination with an organic solvent,6 while Zn–proline
promotes the aldol reaction in aqueous media with moderate
enantioselectivity (up to 56% ee).7 Organocatalysts have been
reported to promote the enantioselective, direct aldol reaction in
organic solvents,8 reactions which in some cases proceed with
water present,9 though the organic solvent is still required. The first
aldol reactions to use only water as solvent were reported
independently by Barbas’ and our groups. Barbas et al. used a
diamine with a long alkyl chain and an acid as a co-catalyst,
the reaction proceeding in an emulsion.10 Our group has developed
a highly lipophilic siloxyproline catalyst,11 and a combined
Though a suitable catalyst was discovered, monitoring of the
progress of the reaction was difficult because the reaction mixture
became cloudy in a short reaction time. Moreover it is difficult to
distinguish the reaction in water and that in the organic phase once
the reaction mixture becomes cloudy. Thus, a detailed investiga-
tion was performed under more dilute conditions (2 mol L21), in
which homogeneous reaction continues for a longer reaction
time.{ It was observed that propanal and Pro–NH2 dissolved in
water, generating a clear, homogeneous solution without forming
a biphase or an emulsion at the beginning. After stirring the
aqueous propanal solution (2 mol L21) with a catalytic amount of
Pro–NH2 for 2.5 h at room temperature (Fig. 1), the aldol product
was obtained in 40% yield with good enantioselectivity (Table 1,
entry 20). From this time, formation of small, oily particles started,
making the reaction mixture cloudy. This oily phase consisted of
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: Typical proce-
dure of asymmetric self-aldol reaction of propanal (Table 1, entry 19). See
DOI: 10.1039/b702559a
2524 | Chem. Commun., 2007, 2524–2526
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or kinetic resolution in the dehydration reaction proceeded. For
the first 2.5 h, propanal is completely dissolved in D2O, and was
found by 13C NMR to exist together with its hydrated form in a
ca. 1 : 1 ratio throughout the course of the reaction. The aldol
product, however, is not hydrated. Therefore during this time all
the reagents are dissolved in water homogeneously with the
formation of only a small amount of hydrophobic 2-methylpent-2-
enal. Thus, the aldol reaction of propanal proceeds ‘‘in water’’ and
not ‘‘in the organic phase’’ at least for the first 2.5 h. This is the
first such asymmetric aldol reaction, proceeding ‘‘in water’’ with
good enantioselectivity.
Pro–NH2 in water and Pro in DMF8c afforded the aldol
products with the same absolute configuration, indicating that an
amide proton of Pro–NH2 likely activates the carbonyl group in
the same way as does the carboxylic acid proton of Pro. As the
asymmetric aldol reaction due to Pro is thought to proceed via an
enamine mechanism, the present Pro–NH2 mediated reaction
likely proceeds via the same manner.
Fig. 1 Reaction mixture of the aldol reaction of propanal catalyzed by
Pro–NH2 after stirring for 2.5 h (left) and 24 h (right) at room
temperature.
2-methylpent-2-enal, the dehydrated aldol adduct. After stirring
for 24 h (Fig. 1), the aldol product was isolated in 29 and 9% yield
from the water and the oily phase respectively, with lower
enantioselectivity, while 2-methylpent-2-enal was isolated in 13 and
43% yield from the water phase and the oily phase, respectively
(Table 1, entry 21). The reason why the yields of the aldol product
at 2.5 h and 24 h are nearly the same is owing to this dehydration
side reaction. The fact that enantioselectivities of the aldols at 24 h
are low compared with those at 2.5 h indicates that racemization
Next the effect of concentration was examined (Table 2). The
reaction scarcely proceeds when performed under neat conditions,
indicating that the presence of water is essential. On the other
hand, the yield was decreased when an excess amount of water
(100 equiv.) was employed, because the reagents were diluted. This
is also evidence that the reaction proceeds in the aqueous phase. A
moderate yield was obtained in the presence of 50 equiv. of water.
Good enantioselectivity was obtained regardless of the concentra-
tion. This is a marked contrast to the proline-mediated aldol
reaction, in which the addition of water severely compromises the
enantioselectivity.8b It was suspected that the addition of an amine
to an aqueous mixture leads to raising of pH, promoting the non-
enantioselective aldol reaction by the general base mechanism,
with the results of decreased enantioselectivity.4 The fact that the
enantioselectivity is not affected by the amount of water would be
a piece of evidence that the reaction in water proceeds by the
enamine mechanism rather than by the general base mechanism.
Though it is known that aldehyde and amine can react to
generate an enamine under aqueous conditions when an organic
solvent is present, this is the first result showing that this can occur
in a clear water solution without addition of any such solvent, and
that the enamine generated can react with a further molecule of
aldehyde with high enantioselectivity. Moreover, the present
catalyst may have been present on the early Earth, generated
from optically-enriched Pro and ammonia by a non-enzymatic
reaction, and we have demonstrated that Pro of very high optical
Table 1 Effect of amino acid, amino amide, or dipeptide as catalyst
of the self-aldol reaction of propanal in watera
Yieldb
Time/h (%)
ee 1d ee 2d
Entry Catalyst
syn : antic (%)
(%)
1
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
3
,3
,3
7
ND
ND
ND
214
4
ND
ND
218
210
28
L-Ala
2
ND
L-Pro
3
1.2 : 1
1 : 1
L-Met
4
11
15
,3
,3
15
,3
11
18
32
41
,3
21
32
29
21
41
40
38f
L-Lys
5
1 : 1.8
214
ND
ND
3
L-Arg
6
ND
ND
ND
ND
18
L-Asn
7
L-Glu
8
1 : 1
ND
1 : 1
L-Ala-L-Ala
L-Pro-L-Ala
L-Pro-L-Val
L-Ala–NH2
L-Phe–NH2
L-Tyr–NH2
L-Glu–NH2
L-Trp–NH2
L-Thr–NH2
L-His–NH2
L-Val–NH2
L-Pro–NH2
L-Pro–NH2
L-Pro–NH2
9
ND
62
ND
48
10
11
12
13
14
15
16
17
18
19
20e
21e
a
1.2 : 1
1.1 : 1
1.1 : 1
ND
11
28
12
256
253
ND
252
13
213
ND
14
Table 2 Effect of solvent and concentration on the self-aldol reaction
of propanala
1 : 1
Yieldb
Entry Solvent Concentration (%)
ee 1d ee 2d
1.5 : 1
1.1 : 1
1.7 : 1
1.1 : 1
1.1 : 1
1.1 : 1
9
syn : antic (%)
(%)
8
235
234
78
46
1
2
3
4
5
6
a
Neate
Water
Water
Water
Water
Water
0
29
31
23
48
14
74
1 equiv.f
5 equiv.
20 equiv.
50 equiv.
100 equiv.
1.1 : 1
1.1 : 1
1.3 : 1
1 : 1
66
69
74
67
68
69
67
78
67
68
2.5
24
74
78
45
36
The reaction was conducted with 0.15 mmol of catalyst, 3.0 mmol
of propanal, and 0.33 mL of water at room temperature, otherwise
noted. ND indicates not determined. Isolated yield. Determined
1 : 1
b
c
The reaction was conducted with 0.15 mmol of Pro–NH2, 3.0 mmol
by 1H NMR. Determined by chiral HPLC after conversion to the
d
of propanal, and water as indicated at room temperature for 3 h.
e
benzoyl ester. The reaction was performed using 1.5 mL of water
b
c
d
Isolated yield. Determined by 1H NMR. Determined by chiral
HPLC after conversion to the benzoyl ester. The reaction was
(2 mol L21), and see text. 2-Methylpent-2-enal was generated in
56% yield, see text.
f
e
f
conducted without solvent. The equivalents of water to propanal.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 2524–2526 | 2525

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J., 2006, 12, 5954. Recent examples: (d) T. Hamada, K. Manabe,
purity can be generated from Pro of very low optical purity under
certain reaction conditions.17 The good enantioselectivity induced
by Pro–NH2 is remarkable when compared with the enantioselec-
tivity (10–15%) catalyzed by the previously examined catalysts
plausibly present in the prebiotic environment.14,18,19
S. Ishikawa, S. Nagayama, M. Shiro and S. Kobayashi, J. Am. Chem.
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Though there is a room for the improvement in the yield,
diastereo-, enantio-selectivities, and generality, the present reaction
is the first example that a small organic molecule (MW = 66) can
catalyze the asymmetric, direct aldol reaction ‘‘in water’’.
This work was partially supported by the Toray Science
Foundation and a Grand-in-Aid for Scientific Research from
The Ministry of Education, Culture, Sports, Science, and
Technology (MEXT).
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Notes and references
{ Typical procedure of asymmetric self-aldol reaction of propanal (Table 1,
entry 20).
To a 2 mol L21 propanal aqueous solution (1.5 mL, 3.0 mmol) was
added L-proline carboxamide (17 mg, 0.15 mmol) at room temperature.
After stirring the reaction mixture for 2.5 h, the reaction mixture was
cooled at 0 uC and MeOH (3 mL) and NaBH4 (284 mg, 7.5 mmol) were
added. The reaction mixture was stirred for 1 h at 0 uC. The reaction was
quenched with pH 7.0 phosphate buffer solution and the organic materials
were extracted with ethyl acetate three times and the combined organic
extracts were dried over anhydrous Na2SO4, and concentrated in vacuo
after filtration. Purification by silica gel column chromatography (ethyl
acetate–hexane = 1 : 2 A 1 : 1) gave (2R,3R)-2-methylpentane-1,3-diol and
(2R,3S)-2-methylpentane-1,3-diol (diastereomer ratio = 1.1 : 1, 73 mg,
0.6 mmol) in 40% yield.
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IA column (100 : 1 hexane : 2-propanol, l = 254 nm), 1.0 mL min21; major
enantiomer (syn) tr = 24.6 min, minor enantiomer (syn) tr = 29.9 min, major
enantiomer (anti) tr = 31.5 min, minor enantiomer (anti) tr = 34.4 min, after
conversion to their mono benzoyl esters.
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2526 | Chem. Commun., 2007, 2524–2526
This journal is ß The Royal Society of Chemistry 2007