Organocatalytic direct asymmetric aldol reactions in water

Article abstract of DOI:10.1021/ja0573312

We have developed direct asymmetric cross-aldol reactions that can be performed in water without addition of organic solvents. A bifunctional catalyst with a long hydrophobic alkyl chain efficiently catalyzed the reactions and afforded the desired aldol p

Full text of DOI:10.1021/ja0573312

Published on Web 12/31/2005
Organocatalytic Direct Asymmetric Aldol Reactions in Water
Nobuyuki Mase,† Yusuke Nakai,† Naoko Ohara,† Hidemi Yoda,† Kunihiko Takabe,*,†
Fujie Tanaka,‡ and Carlos F. Barbas III*,‡
Department of Molecular Science, Faculty of Engineering, Shizuoka UniVersity, 3-5-1 Johoku, Hamamatsu
432-8561, Japan and The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular
Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received October 27, 2005; E-mail: tcktaka@ipc.shizuoka.ac.jp; carlos@scripps.edu
Table 1. Screening of Catalysts in the Direct Asymmetric Aldol
Reaction of Cyclohexanone (1a) with p-Nitrobenzaldehyde (2a) in
Watera
Catalytic asymmetric reactions that can be performed in water
are of current interest, because water is a desirable solvent with
respect to environmental concerns, safety, and cost.1 However, the
use of water as reaction solvent is not always practical for
asymmetric catalytic reactions because water often inhibits the
catalyst’s activity or alters enantioselectivity by interrupting ionic
interactions and hydrogen bonds critical for stabilizing the transition
states of the reactions.1 Thus, special design is required for
performing asymmetric reactions in water. Here we report efficient
enamine-based organocatalytic direct asymmetric aldol reactions
in water without any organic cosolvent. Reactions afforded the
desired products in high yields with high enantioselectivities using
an amine-acid bifunctional catalyst.
Organocatalytic asymmetric aldol reactions via in situ generated
enamine intermediates are useful C-C bond-forming reactions and
yield aldol products with excellent enantioselectivities.2 These
reactions are typically performed in organic solvents, such as
DMSO, DMF, or chloroform, under mild conditions. Although
addition of a small amount of water often accelerates reactions and/
or improves enantioselectivities,3 addition of a large amount of water
or aqueous buffer as reaction solvent has typically resulted in low
yield with low or no enantioselectivity.2a,3b,4 In contrast, natural
Class I aldolase enzymes5 and aldolase catalytic antibodies6 that
use an enamine mechanism catalyze enantioselective aldol reactions
in water. In the aldolase antibodies, the reactions occur in a
hydrophobic active site,6 indicating that diminishing contacts
between bulk water and the reaction transition states may be critical
for high enantioselectivities. Thus, we hypothesized that a small
organic catalyst with appropriate hydrophobic groups should
assemble with hydrophobic reactants in water and sequester the
transition state from water. As a result, the outcome of the reaction
should be similar to that performed in organic solvents. To test
this hypothesis, the aldol reaction of cyclohexanone (1a) and
p-nitrobenzaldehyde (2a) to afford 3a was performed in water using
several amine catalysts bearing hydrophobic alkyl chains in the
presence or absence of additives. While the organocatalytic aldol
reaction between 1a and 2a has typically been performed using a
large excess of 1a,2a,4 here, only 1 or 2 equiv of cyclohexanone to
the aldehyde were used. The results are shown in Table 1.
Although L-proline (4) catalyzed the aldol reaction in DMSO
(entry 1), no reaction progress was detected after 4 days in water
(entry 2). (S)-Prolinol (5) and amide catalyst 6a both catalyzed the
reaction, but low enantioselectivities were observed (entries 3 and
4). The reaction with amide catalysts 6b or 7 bearing long alkyl
groups afforded better enantioselectivity than the reaction with 6a,
but the enantiomeric excess was still poor (entries 5 and 6). Diamine
8a also afforded product 3a in quantitative yield in water without
an acid additive, but the product was racemic (entry 7). Diamine
entry
catalyst
additive
time (h)
yield (%)
anti:synb
eec (%)
1d
2
4
24
96
5
65
0
63:37
89
4
3
5
77e
68e
78e
99
99
99
0
75:25
84:16
84:16
79:21
77:23
71:29
4
3
4
6a
6b
7
5
5
5
22
36
0
6
5
7
8a
8a
8a
8b
8b
8b
8b
8b
8b
8b
5
8d
9
TFA
TFA
24
96
5
55
10
11
12
13
14d
15g
16h
99
81
99
94
99
99
98
94:6
1
21
85
93
87
94
92
AcOH
(+)-CSAf
Sc(OTf)3
TFA
TFA
TFA
24
24
24
24
24
48
60:40
68:32
84:16
82:18
89:11
85:15
a Conditions: Amine catalyst (0.05 mmol), additive (if used, 0.05 mmol),
1a (1.0 mmol), and 2a (0.5 mmol) in water (1.0 mL). Determined by H
b
1
c
NMR of the crude product. Determined by chiral-phase HPLC analysis
for anti-product. dThe reaction was carried out in DMSO. Aldehyde 2a
e
recovery was 21%, 18%, and 11%, respectively. fD-(+)-10-Camphorsulfonic
g
h
acid. See ref 9. Donor 1a (0.5 mmol, 1 equiv) was used.
8a with trifluoroacetic acid (TFA)7 efficiently catalyzed the reaction
in DMSO but not in water (entries 8 and 9).
The best result with respect to yield, diastereoselectivity, and
enantioselectivity was observed with catalyst 8b8 and TFA additive
(entry 15). In water without any additive, the reaction with 8b gave
3a in good yield with high diastereoselectivity but with almost no
enantioselectivity (entry 10). Addition of TFA to the reaction with
8b significantly improved the enantioselectivity to 94% ee for anti-
3a (entry 15).9 Addition of a Lewis acid, such as scandium
trifluoromethanesulfonate, to the reaction catalyzed by 8b afforded
the product 3a with 93% ee (entry 13). Strong acids provided higher
enantioselectivities than a weak acid (entries 12-15 vs 11). The
results of the 8b/TFA-catalyzed reaction in water vs DMSO were
similar; the reaction in water afforded slightly higher diastereo-
and enantioselectivities than that in DMSO (entry 14 vs 15). The
diastereoselectivity of the 8b/TFA-catalyzed reaction was higher
than that of the L-proline-catalyzed reaction (entry 1 vs 15).2a,4e In
† Shizuoka University.
‡ The Scripps Research Institute.
9
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J. AM. CHEM. SOC. 2006, 128, 734-735
10.1021/ja0573312 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Diamine 8b/TFA-Catalyzed Aldol Reactions of 1a with
Various Arylaldehydes 2 in Watera
Table 3. Diamine 8b/TFA-Catalyzed Aldol Reactions of Various
Ketones and Aldehyde 1 with 2a in Watera
R1
R2
product
time (h)
yield (%)
anti:synb
eec (%)
entry
X
product
time (h)
yield (%)
anti:synb
eec (%)
entry
1
2
3
4
5
6
7
8
4-CN
4-CO2Me
4-Br
3b
3c
3d
3e
3f
3g
3h
3i
48
48
72
72
72
72
24
24
99
89
43d
74d
46
5
86:14
90:10
91:9
88:12
90:10
86:14
90:10
89:11
87
91
97
90
99
96
99
98
1
-(CH2)3-
3j
3k
3l
3m
3n
3o
24
72
72
72
72
72
98
61:39
46:54
87
2d
3d
4d
5
-(CH2)5-
40
99e
55
Me
Et
nHex
H
H
82f
49f
99g
99i
4-Cl
H
54
4-H
H
22g
91i
6
noteh
4-OMe
3-NO2
2-NO2
99
98
a See ref 9. bDetermined by 1H NMR of the crude product. cDetermined
by chiral-phase HPLC analysis for anti-product. dCatalyst (0.3 equiv) was
used. eFor syn-product. Anti-product was obtained with 23% ee. fAldehyde
2a recovery was 10% and 45%, respectively. gIn DMSO, 14% yield, 29%
ee. hIsobutyraldehyde was used as a donor. iIn DMSO, 96% yield, 90% ee.
a See ref 9. bDetermined by 1H NMR of the crude product. cDetermined
by chiral-phase HPLC analysis for anti-product. d Aldehyde was recovered
in 40% and 18%, respectively.
addition, the amount of donor cyclohexanone could be decreased
to 1 equiv relative to the acceptor aldehyde without compromising
the results (entry 16). This is a significant improvement over the
conventional aldol reaction in organic solvents, in which a
considerable excess of donor (20 vol %, 19 equiv) was used.2-4
Furthermore, crude aldol products were easily isolated by removal
of water using centrifugal separation.
demonstrated excellent reactivity, diastereoselectivity, and enanti-
oselectivity in water. Further studies focusing on the full scope of
this catalyst-aqueous media system and related systems are currently
under investigation and will be reported in due course.
Acknowledgment. This study was supported in part by a Grant-
in-Aid (No.16550032) from Scientific Research from the Japan
Society for the Promotion of Science and The Skaggs Institute for
Chemical Biology.
These results indicate that neither an acid functionality on the
pyrrolidine derivatives nor an acid additive are required for catalysis
of the aldol reaction in water. When catalyst or catalyst additive
included an acid but not a hydrophobic alkyl chain, the reaction
did not proceed in water. This may be because both catalyst and
additive are soluble, whereas reactants are less miscible in water.
In a biphasic system, interactions required for reaction do not occur.
In the case of the reaction using 8b/TFA, the catalyst additive
assembles with the reactants through hydrophobic interactions,
excluding water molecules from the organic phase.10 In this
concentrated organic phase the reaction occurs efficiently to afford
3a with high enantioselectivity, presumably facilitated by hydrogen
bonds between the enamine-8b/TFA ammonium salt and the
acceptor in the transition state. In fact, the reaction mixture
containing 1a, 2a, and 8b/TFA was not biphasic but was an
emulsion (see Supporting Information). Note that L-proline- or 8a-
catalyzed aldol reactions in aqueous micelles using surfactants, such
as sodium dodecyl sulfate (SDS), only gave racemic products.4a,c
The major product 3a generated from the 8b/TFA-catalyzed
reaction had (2S,1′R)2a absolute stereochemistry. Therefore, the
enamine intermediate of the 8b/acid-catalyzed reaction favored a
re-facial attack on the arylaldehyde. This reaction mode is in accord
with that of diamine 8a/acid-catalyzed and L-proline-catalyzed aldol
reactions in DMSO.2a,7,11
The scope of this class of aldol reactions using diamine 8b/TFA
catalyst in water was examined with a series of arylaldehyde
acceptors (Table 2) and ketone and aldehyde donors (Table 3). In
most cases, reactions afforded anti-aldol products in high yields
with excellent enantioselectivities (Table 2). Reactions with water
miscible ketones yielded the products in moderate yield even when
0.3 equiv of catalyst was used (Table 3, entries 3 and 4), while
quantitative yield was observed in the reaction with less miscible
2-octanone (entry 5). The reaction of isobutyraldehyde yielded R,R-
dialkyl aldol product 3o, with no formation of self-aldol product,
and with similar high enantioselectivity compared with the reaction
in DMSO (entry 6).
Supporting Information Available: Experimental procedures and
HPLC data and a photograph of the reaction mixture. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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(7) Diamine 8a/acid bifunctional catalysts catalyzed aldol reactions with high
enantioselectivities in conventional organic solvents. (a) Nakadai, M.;
Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167-8177. (b) Mase,
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8b (0.05 mmol) in water (1.0 mL) trifluoroacetic acid (0.05 mmol) was
added at 25 °C under air. The reaction mixture was stirred for 3 min in
a closed system, and ketone (1.0 mmol) and aldehyde (0.5 mmol) were
added. The reaction mixture was vigorously stirred for the indicated time.
Removal of water by centrifugal separation and purification of crude
product by column chromatography afforded the aldol product.
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aldol reaction that can be performed in water without addition of
organic solvents. The diamine 8b/TFA bifunctional catalyst system
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