Highly diastereo- and enantioselective direct aldol reactions of aldehydes and ketones catalyzed by siloxyproline in the presence of water

Article abstract of DOI:10.1002/chem.200700363

Proline-based organocatalysts have been developed for a highly enantioselective, direct aldol reaction of aldehydes and ketones in the presence of water. While several surfactant-proline combined catalysts have proved effective, proline derivatives with a hydrophobic moiety such as rraw-siloxy-L-proline and cis-siloxy-D-proline, both of which are easily prepared from the same commercially available 4-hydroxy-L-proline. have been found to be the most effective organocatalysts examined in this study, affording the aldol product with excellent diastereo- and enantioselectivities, these two catalysts generating opposite enantiomers. Water affects the selectivity, and poor results are obtained under neat reaction conditions or in dry organic solvents. More than three equivalents of water are required for the best diastereo- and enantioselectivities. while three equivalents is the recommended amount from a synthetic point of view. The reaction proceeds in the organic phase, and also proceeds in the presence of a large amount of water. The large-scale preparation of aldols with the minimal use of an organic solvent, including in the purification step. is described.

Full text of DOI:10.1002/chem.200700363

DOI: 10.1002/chem.200700363
Highly Diastereo- and Enantioselective Direct Aldol Reactions of Aldehydes
and Ketones Catalyzed by Siloxyproline in the Presence of Water
Seiji Aratake, Takahiko Itoh, Tsubasa Okano, Norio Nagae, Tatsunobu Sumiya,
Mitsuru Shoji, and Yujiro Hayashi*[a]
Abstract: Proline-based organocata-
lysts have been developed for a highly
enantioselective, direct aldol reaction
of aldehydes and ketones in the pres-
ence of water. While several surfac-
tant–proline combined catalysts have
proved effective, proline derivatives
with a hydrophobic moiety such as
trans-siloxy-l-proline and cis-siloxy-d-
proline, both of which are easily pre-
pared from the same commercially
available 4-hydroxy-l-proline, have
been found to be the most effective or-
ganocatalysts examined in this study,
affording the aldol product with excel-
lent diastereo- and enantioselectivities,
these two catalysts generating opposite
enantiomers. Water affects the selectiv-
ity, and poor results are obtained under
neat reaction conditions or in dry or-
ganic solvents. More than three equiva-
lents of water are required for the best
diastereo- and enantioselectivities,
while three equivalents is the recom-
mended amount from a synthetic point
of view. The reaction proceeds in the
organic phase, and also proceeds in the
presence of a large amount of water.
The large-scale preparation of aldols
with the minimal use of an organic sol-
vent, including in the purification step,
is described.
Keywords: aldol reaction · asym-
metric synthesis · organocatalysis ·
proline · sustainable chemistry ·
water
Introduction
quire toxic, rare, and/or expensive metals, and suffer from
possible metal contamination of the products. Organocata-
lysts,[6] in contrast, are free from these problems and, more-
over, are inexpensive and stable to moisture and air. Thus,
the development of small organic molecules capable of cata-
lyzing enantioselective reactions using water as the reaction
medium is currently a highly sought-after goal.
Processes using water as a reaction medium have recently
attracted a great deal of attention,[1] because water possesses
unique properties as a solvent. For example, Breslow et al.
reported that the Diels–Alder reaction is accelerated in
water under dilute conditions,[2] while Sharpless et al. report-
ed that some organic reactions are accelerated under so-
called “on water” conditions.[3]
The synthesis of enantiopure molecules is another impor-
tant issue,[4] and the development of enantioselective reac-
tions using water as a reaction medium is being intensively
investigated,[5] although it was long thought that such reac-
tions were mainly confined to the realm of enzymes. Suc-
cessful catalytic versions of enantioselective reactions are
mostly reliant upon transition metal complexes, and may re-
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.[7] In nature,
type I and type II aldolases catalyze this reaction in an aque-
ous environment with perfect enantiocontrol by way of an
enamine mechanism and by using a zinc cofactor, respec-
tively.[8] The catalytic, direct asymmetric aldol reaction is an
active research field, and excellent results have been report-
ed in an organic solvent using organometallic catalysts,[9]
while the development of this reaction using water as a sol-
vent has also been intensively investigated. Chiral Lewis
acids have been developed for the aqueous Mukaiyama
aldol reaction, an indirect method using a silyl enol ether
whereby water is used as a co-solvent with organic sol-
vents.[10] Kobayashi reported the use of a chiral Lewis acid–
surfactant combined catalyst in the Mukaiyama aldol reac-
tion using water as the only solvent, in which a moderate
enantioselectivity was attained.[11] A Zn-proline-catalyzed
[a] S. Aratake, T. Itoh, T. Okano, N. Nagae, T. Sumiya, Dr. M. Shoji,
Prof. Dr. Y. Hayashi
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162–8601 (Japan)
Fax : (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
aldol reaction in aqueous media, in which a mixture of ace-
tone and water was used as the solvent, proceeded with a
moderate enantiomeric excess.[12] In this reaction, acetone
acts not only as the nucleophile, but also as a co-solvent.
List, Lerner, and Barbas discovered the proline-mediated
aldol reaction in 2000.[13] Since then, many organocatalysts
have been developed for several asymmetric reactions.[6,14]
Proline is capable of catalyzing the direct aldol reaction in
polar organic solvents such as DMSO and DMF.[13,15,16] Re-
cently, Bolm and co-workers reported that proline catalyzes
a solvent-free asymmetric aldol reaction involving the use of
a ball-mill.[17] When the reaction was performed in the pres-
ence of water or a buffer solution, a nearly racemic product
was obtained.[18] Though several chiral organocatalysts have
been developed for the aldol reaction, and some of them
provide aldols enantioselectively in aqueous organic sol-
vents,[19] they still require an organic co-solvent. It has been
demonstrated by Jandaꢁs[20] and Barbasꢁ[16] groups that the
enamine, which had been considered to be easily hydrolyzed
in the presence of water, is in fact generated and reacts with
an electrophile to afford an aldol under aqueous conditions.
However, it is very difficult to attain high enantioselectivity
under aqueous conditions; Janda et al. used nornicotine as a
catalyst with 10% DMSO, which afforded some asymmetric
induction (ꢀ20% ee).[20] Barbas et al. reported that the
aldol reaction of acetone and p-nitrobenzaldehyde proceeds
using proline in 20 vol% water, affording the aldol product
with between 10 and 20% ee, while good enantioselectivity
is obtained using DMSO as the solvent.[16] Pihko et al. re-
ported a highly enantioselective aldol reaction in aqueous
DMF, in which the reaction proceeds efficiently in the pres-
ence of a large excess of water.[19k] Though Chimni et al. re-
ported that proline and its derivatives act as catalysts in the
presence of water, the highest enantioselectivity achieved
was just 62%.[21] As far as we are aware, only enzymes and
antibodies of very high molecular weight have hitherto been
shown to catalyze the direct aldol reaction with high enan-
tioselectivity in purely aqueous media. Moreover, a rather
high catalyst loading is usually required for these organoca-
talyst-mediated aldol reactions. At the same time as our pre-
liminary publication on the asymmetric aldol reaction of al-
dehydes and ketones using siloxyproline in the presence of
water,[22] Barbas and co-workers reported an asymmetric
aldol reaction performed in the presence of water, in which
the catalyst system used consisted of a combination of a di-
water, though the enantioselectivities were moderate.[25] Just
recently, we found that proline amide acts effectively “in
water”, rather than “in the presence of water”.[26] Since our
first publication, a couple of asymmetric aldol reactions cat-
alyzed by an organocatalyst and proceeding in the presence
of water have appeared.[27]
As there is some confusion over the term “in water”,[28,29]
we would like to use it for reactions in which the participat-
ing reactants are homogeneously dissolved in water.[29]
Throughout this paper, the term “in the presence of water”
is used for a reaction that proceeds in a concentrated organ-
ic phase with water being present as the second phase,
which influences the reaction in the organic phase.[29]
Herein, we disclose full details of our enantioselective aldol
reaction of ketones and aldehydes catalyzed by siloxyproline
in the presence of water.
Results and Discussion
Catalyst preparation: The aldol reaction of cyclohexanone
and benzaldehyde was selected as a model. The organocata-
lysts that have been investigated in this study are summar-
ized in Scheme 1. The pyrrolidin-2-yl-1H-tetrazole catalyst
Scheme 1. Organocatalysts examined in this study. TBS=tert-butyldime-
thylsilyl, TIPS=triisopropylsilyl, TBDPS=tert-butyldiphenylsilyl.
ACHTREUNG
amine with a long alkyl chain and trifluoroacetic acid.[23] We
also reported that a surfactant–proline combined catalyst is
effective in the direct, enantioselective aldol reaction of two
aldehydes, which proceeds in the presence of water.[24] Re-
cently, we also reported that proline itself promotes the
enantioselective aldol reaction without any organic solvent
under neat conditions, and in the presence of three equiva-
lents of water for aldehyde–aldehyde and aldehyde–ketone
aldol reactions, respectively, when the reaction proceeds ef-
ficiently by virtue of reactive electrophilic aldehydes.[25] We
also found that proline could catalyze the enantioselective
aldol reaction even in the presence of a large amount of
(3)[19a,30] and pyrrolidine sulfonamide catalysts 5[31] were pre-
pared according to the relevant literature procedures. The 4-
acyloxyproline catalysts (4a–f) were prepared from the
known benzyl ester of Z-4-hydroxyproline,[32] which is easily
prepared from commercially available trans-4-hydroxy-l-
proline; 4a–f were prepared by first treating the benzyl
ester with the appropriate acyl chlorides and pyridine to
give 9a–f, which were then subjected to hydrogenolytic de-
benzylation (Scheme 2). Pyrrolidines bearing an N-sulfonyl-
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Y. Hayashi et al.
Scheme 2. Synthetic scheme for acyloxyprolines 4: a) acyl chlorides, DMAP (cat.), pyridine, 08C to room temperature; b) H2, Pd(OH)2, EtOAc, room
temperature
Table 1. The effect of catalyst on the reaction yield and selectivity.[a]
carboxyamide moiety 6 were synthesized by reaction of the
4-nitrophenyl ester of Z-proline 10 with the appropriate sul-
fonylamides to give 11, followed by hydrogenolysis[33]
(Scheme 3). The trans-siloxy-l-proline catalysts 7a–c were
prepared by first treating the benzyl ester of Z-4-hydroxy-
proline with the appropriate silyl chlorides and imidazole to
give 12a–c, followed by hydrogenolysis (Scheme 4). The cis-
siloxy-d-proline 8 was prepared according to the literature
procedure.[34]
Entry
Catalyst
Yield [%][b]
anti:syn[c]
ee [%][d]
[e]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
proline (1)
hydroxyproline (2)
<5
<5
<5
53
48
37
18
30
38
65
62
20
62
22
61
71
78
70
N.D.
N.D.[e]
N.D.[e]
N.D.[e]
99
99
98
98
97
89
82
89
87
98
97
>99
>99
>99
ꢁ98
[e]
N.D.
[e]
3
N.D.
4a
4b
4c
4d
4e
4 f
5a
5b
5c
6a
6b
7a
7b
7c
8
20:1
17:1
15:1
17:1
10:1
Catalyst screening: The aldol reaction of benzaldehyde
(1 equiv) and cyclohexanone (5 equiv) was performed using
10 mol% of the organocatalyst in the presence of water
(18 equiv) for 18 h at room temperature. The results for the
organocatalysts investigated are summarized in Table 1. Pro-
line (1) was found not to promote the reaction, as was re-
ported by Barbas and co-workers.[18] Neither did hydroxy-
proline (2) prove effective. The pyrrolidin-2-yl-1H-tetrazole
catalyst (3), which has been reported to promote the aldol
reaction of chloral under aqueous conditions[19a] and several
other organic reactions,[30] does not catalyze the reaction
under the present reaction conditions.
As Kobayashi and co-workers reported that surfactant-
combined Lewis acids can be effective catalysts under aque-
ous conditions,[10p] we prepared several types of surfactant–
proline combined organocatalysts. 4-Acyloxyprolines 4 with
different side chains ranging from hexanoyloxy to hexadeca-
noyloxy were examined. It was found that these 4-acyloxy-
prolines catalyze the aldol reaction in the presence of water,
and the aldol product was thereby obtained in moderate
yield with excellent diastereo- and enantioselectivities. The
length of the acyl side chain affected the yield, the best re-
sults being obtained when the organocatalyst 4a bearing the
hexanoyloxy moiety was employed.
9:1
2.3:1
2.6:1
3:1
>20:1
>20:1
19:1
14:1
13:1
>20:1
[a] The reaction was performed by employing benzaldehyde (0.4 mmol),
cyclohexanone (2.0 mmol), organocatalyst (0.04 mmol), and water
(0.13 mL) at room temperature for 18 h. [b] The combined isolated yield
of the diastereomers. [c] The diastereoselectivity was determined by 1H
NMR analysis of the reaction mixture. [d] Optical yield refers to that of
the anti isomer, which was determined by HPLC analysis on a chiral
phase. [e] N.D.=not determined.
We also prepared some other types of surfactant–proline
combined catalysts, including pyrrolidines bearing a sulfon-
AHCTREaUNG mide moiety 5. The pyrrolidine sulfonamide 5a has been
reported to be an effective catalyst in the Michael reaction
of nitroalkenes.[31] We found that the enantioselective aldol
Scheme 3. Synthetic scheme for proline sulfonamides 6: a) sulfonamides, NaH, DMF, room temperature; b) H2, 10% Pd/C, MeOH, room temperature.
Scheme 4. Synthetic scheme for siloxyprolines 7: a) R-Cl, DMAP (cat.), imidazole, DMF, 08C to room temperature, or R-OTf, 2,6-lutidine, 08C to room
temperature; b) H2, 10% Pd/C, MeOH, room temperature.
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Siloxyproline-Catalyzed Aldol Reactions
FULL PAPER
Table 2. The effect of solvent on the aldol reaction catalyzed by siloxy-
reaction was catalyzed by these catalysts in the presence of
water, but that the diastereoselectivity was low and the
enantioselectivity was less than 90%. The third type of sur-
factant–proline combined catalysts that we prepared were
pyrrolidines bearing an N-sulfonylcarboxamide moiety 6.
The corresponding N-tosylcarboxamide has been reported
to promote the aldol reaction of acetone with p-nitrobenzal-
dehyde in an organic solvent to afford the product with ex-
cellent enantioselectivity.[33] The length of the alkyl chain
had a significant effect on the yield. The organocatalyst with
an octylsulfonyl moiety, 6a, produced a good yield with ex-
cellent diastereo- and enantioselectivities, while that with
the dodecylsulfonyl moiety, 6b, provided a low yield albeit
with excellent selectivity.
In further screening of organocatalysts, we also investigat-
ed trans-siloxy-l-prolines 7, which we found to be more re-
active than proline in a-aminoxylations and three-compo-
nent Mannich reactions.[35] To our surprise, though siloxy-
prolines 7 do not possess a long alkyl chain necessary for
surfactant character, they efficiently promote the aldol reac-
tion in a highly diastereo- and enantioselective manner. Not
only the TBS-substituted proline 7a, but also the TIPS- and
TBDPS-substituted derivatives 7b and 7c proved to be ef-
fective. On increasing the hydrophobicity of the siloxy
group the yield increased, and in the reaction catalyzed by
the TBDPS-substituted proline 7c, a good yield (78%) was
obtained with excellent anti-selectivity and nearly perfect
enantioselectivity.
Not only the trans-siloxy-l-prolines 7, but also the cis-
siloxy-d-proline 8 was found to be an effective organocata-
lyst, promoting the aldol reaction in good yield with the
same excellent selectivity, while generating the opposite en-
antiomer of the product to trans-siloxy-l-proline 7c. cis-
Siloxy-d-proline 8 may be synthesized from trans-4-hydroxy-
l-proline, the same starting material as for the synthesis of
the trans-siloxy-l-proline, by routine published proce-
dures.[34] While trans-4-hydroxy-l-proline is inexpensive, its
enantiomer, trans-4-hydroxy-d-proline, is very expensive.
Therefore, either enantiomer of the aldol product may be
easily synthesized by judicious choice of either trans-siloxy-
l-proline 7 or cis-siloxy-d-proline 8, both of which are avail-
able from the same inexpensive starting material.
proline 7a.[a]
Entry
Solvent
Yield [%][b]
anti:syn[c]
ee [%][d]
1
2
3
4
5
6
7
water
61
61
66
44
47
37
26
19:1
1.8:1
1:1
1.4:1
1.8:1
1.8:1
2.8:1
>99
89
80
87
91
none[e]
DMSO
CH3CN
toluene
hexane
MeOH
87
45
[a] The reaction was performed by employing benzaldehyde (0.4 mmol),
cyclohexanone (2.0 mmol), 7a (0.04 mmol), and solvent (0.4 mL) at room
temperature for 18 h. [b] The combined isolated yield of the diastereo-
1
mers. [c] The diastereoselectivity was determined by H NMR analysis of
the reaction mixture. [d] Optical yield refers to that of the anti isomer,
which was determined by HPLC analysis on a chiral phase. [e] The reac-
tion was performed without solvent.
reaction in organic solvents. Due to its poor solubility in
most such solvents, reactions mediated by proline itself are
restricted to polar organic solvents such as dimethyl sulfox-
ide (DMSO), N,N-dimethylformamide (DMF), and N-meth-
ylpyrrolidone (NMP), while siloxyproline is more soluble
than proline in organic solvents.[35] The reaction proceeded
in the organic solvents examined, though the yield was de-
pendent on the solvent used. In DMSO, a good yield was
obtained but with poor diastereoselectivity and decreased
enantioselectivity (80% ee). In CH3CN, toluene, and
hexane, the enantioselectivities were around 90% and the
diastereoselectivity was low, though a moderate yield was
obtained. In MeOH, which is a protic solvent like water, the
reaction was slow, affording the aldol product in a low yield
and with poor enantioselectivity (45% ee). This is in marked
contrast to the result obtained in the presence of water, a
protic solvent, in which case the aldol product was obtained
with excellent diastereo- and enantioselectivities. The results
summarized in Table 2 suggest that the reaction in the pres-
ence of water is different from that in its absence, and that
compared to organic solvents water has a unique beneficial
effect.
Effect of the amount of water: Employing TBDPS-substitut-
ed siloxyproline 7c as catalyst, the influence of the amount
of water was investigated; the results are summarized in
Table 3. In the presence of only one equivalent of water, the
aldol product was obtained in a good yield with good dia-
stereo- and excellent enantioselectivity. The diastereo- and
enantioselectivities were further improved in the presence
of three equivalents of water, and the same excellent dia-
stereo- and enantioselectivities were attained with even
greater amounts of water. From a synthetic point of view, it
is desirable to use as little water as possible. Thus, three
equivalents of water is the recommended amount. It should
be noted, however, that a large excess of water does not dis-
turb the reaction at all. The reaction proceeds smoothly even
in the presence of 350 equivalents of water to provide the
same excellent selectivity. This is in marked contrast to the
observations of Barbas and co-workers, who found that an
This is the first highly diastereoselective and enantioselec-
tive aldol reaction carried out in the presence of water with-
out using any organic solvent.
Comparison of the reactions performed neat, in organic sol-
vents, and in the presence of water: Excellent results were
obtained in the presence of water using siloxyprolines 7 as
catalysts. We have checked the solvent effect on this aldol
reaction employing the TBS-substituted proline 7a as cata-
lyst; the results are summarized in Table 2. We first exam-
ined the reaction without any addition of water and found
that a low diastereoselectivity and lower enantioselectivity
were obtained, though the yield was moderate. This result
indicates that water is indispensable for achieving excellent
diastereo- and enantioselectivities. Next, we investigated the
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Y. Hayashi et al.
Table 3. The effect of the amount of water present on the aldol reaction
lective aldol reaction of acetone and aldehydes was cata-
lyzed by 2 mol% of proline amide derivatives.[36] In the
present reaction catalyzed by siloxyproline in the presence
of water, only 1 mol% of the siloxyproline 7c is sufficient,
and to the best of our knowledge this is the lowest organo-
catalyst loading for a highly enantioselective aldol reaction.
Next, the amount of cyclohexanone was varied. Up to this
point we had employed five equivalents of ketone when
using 18 equivalents of water, but we found that the reaction
proceeds even with only two equivalents of cyclohexanone
in the presence of three equivalents of water, affording the
aldol with the same excellent diastereo- and enantioselectiv-
ities, whereas a further reduction of the amount of ketone
to 1.2 equivalents reduced the yield and enantioselectivity.
catalyzed by siloxyproline 7c.[a]
Entry
Amount of
water [equiv]
Yield
[%][b]
anti:syn[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
0
1
2
3
5
18
50
100
350
61
87
84
85
79
78
88
84
77
1.8:1
6:1
8:1
12:1
11:1
13:1
12:1
12:1
16:1
89
97
97
98
99
>99
>99
>99
>99
[a] The reaction was performed by employing benzaldehyde (0.4 mmol),
cyclohexanone (2.0 mmol), 7c (0.04 mmol), and various amounts of
water at room temperature for 18 h. [b] The combined isolated yield of
the diastereomers. [c] The diastereoselectivity was determined by 1H
NMR analysis of the reaction mixture. [d] Optical yield refers to that of
the anti isomer, which was determined by HPLC analysis on a chiral
phase.
The effect of water: Of the siloxyprolines 7 employed, the
TBDPS-substituted proline derivative 7c gave the best re-
sults. The appearance of the reaction mixture was rather dif-
ferent for reactions using the other siloxyprolines 7a and
7b. In the presence of 18 equivalents of water, an emulsion
was formed in the case of the TBS derivative 7a, while the
aqueous and organic phases were easily separated in the
case of the reactions of the TIPS and TBDPS derivatives 7b
and 7c (Figure 1). These results indicate that phase separa-
tion becomes easier as the hydrophobicity of the catalyst is
increased.
increase in the amount of water decreases the enantioselec-
tivity of the aldol reaction of acetone and p-nitrobenzalde-
hyde catalyzed by proline.[16]
Effect of the amount of catalyst: Reducing the amount of
catalyst was investigated, and the results are summarized in
Table 4. In the presence of 5 mol% or 3 mol% of the cata-
Table 4. The effect of the amounts of catalyst and ketone on the aldol re-
action catalyzed by siloxyproline 7c.
Entry Amount
of
Amount Amount Time Yield
anti:syn[b] ee
[%][c]
of
of
[h]
[%][a]
catalyst
[mol%]
ketone
[equiv]
water
[equiv]
1[d]
2[d]
3[d]
4[d]
5[e]
6[e]
10
5
3
1
1
5
5
5
5
2
1.2
18
18
18
18
3
18
25
25
48
48
60
78
85
82
76
73
32
13:1
11:1
11:1
10:1
10:1
9.3:1
>99
99
99
99
99
Figure 1. Reaction mixtures of o-chlorobenzaldehyde (1.2 mmol), cyclo-
hexanone (6 mmol), and organocatalysts 7a, 7b, and 7c (0.12 mmol) in
the presence of 18 equivalents of water (0.389 mL) after stirring for 18 h,
then standing for 5 min at room temperature. Left: catalyst 7a. Middle:
catalyst 7b. Right: catalyst 7c.
1
3
93
[a] The combined isolated yield of the diastereomers. [b] The diastereose-
lectivity was determined by 1H NMR analysis of the reaction mixture.
[c] Optical yield refers to that of the anti isomer, which was determined
by HPLC analysis on a chiral phase. [d] The reaction was performed by
employing benzaldehyde (0.4 mmol), cyclohexanone (2.0 mmol), various
amounts of 7c, and water (0.13 mL) at room temperature for the time in-
dicated in the table. [e] The reaction was performed by employing ben-
zaldehyde (2 mmol), cyclohexanone (4.0 or 2.4 mmol), 7c (0.02 mmol),
and water (0.108 mL).
In the presence of a large amount of water, an emulsion
was formed even in the case of the reaction of the TBDPS
catalyst 7c, in which case a good yield and excellent enan-
tioselectivity were obtained (Table 3, entry 9). The solubility
of cyclohexanone in water is 87 gLꢁ1,[39] while that of ben-
zaldehyde is 3 gLꢁ1.[40] Thus, cyclohexanone completely dis-
solves in the presence of 350 equivalents of water, whereas
benzaldehyde does not. Regarding entry 9 of Table 3, it is
surprising that the reaction proceeds smoothly even in the
presence of 350 equivalents of water, because cyclohexa-
none should be completely dissolved in the water at this
concentration. Moreover, we found that the reaction pro-
ceeds with the same efficiency when the reaction mixture is
allowed to stand without stirring except for during the initial
5 min. To explain these unusual phenomena, the reaction in
the presence of 350 equivalents of water was investigated in
lyst 7c, the reaction proceeded smoothly to afford the aldol
product in good yield and with excellent selectivity. Even in
the presence of just 1 mol% of the catalyst, good yields and
excellent diastereo- and enantioselectivities were obtained,
though the reaction proceeds slowly and a longer reaction
time (49 h) is needed. For the proline-mediated aldol reac-
tion, a sub-stoichiometric amount of proline (20–30 mol%)
is usually necessary. As siloxyproline 7 is a reactive catalyst,
the loading of the catalyst could be reduced to just 1 mol%.
Recently, Gong and co-workers reported that the enantiose-
10250
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Siloxyproline-Catalyzed Aldol Reactions
FULL PAPER
detail (Figure 2). Siloxyproline 7c (300 mg), which does not
dissolve in water, was added to a clear solution of cyclohex-
anone (400 mL, 5 equiv) in water (4.86 mL, 100 equiv;
Figure 2 left) forming a suspension. Benzaldehyde (78 mL)
The rates of the reactions in the absence of water or in
the presence of three and 100 equivalents of water were in-
vestigated (Table 5 and Figure 3). All reactions were found
to proceed at a similar rate. Thus, water neither accelerates
nor retards the reaction. When the reaction was performed
without a solvent, low diastereoselectivity and good enantio-
Figure 2. Reaction mixtures of a) cyclohexanone (5 equiv) in water
(350 equiv) (left); b) mixture (a) + siloxyproline 7c (10 mol%) + ben-
zaldehyde (1 equiv), stirring for 5 min (middle); c) after stirring reaction
mixture (b) for 5 min and then standing for 10 min (right); see text for
details.
Table 5. Effect of water on the diastereo- and enantioselectivities of the
aldol reaction catalyzed by siloxyproline 7c.[a]
Entry
Time [h]
Yield [%][b]
anti:syn[c]
ee [%][d]
neat
1
2
3
4
5
3
6
12
24
48
28
41
60
68
72
1.3:1
1.4:1
1.6:1
1.6:1
1.6:1
81
81
82
82
81
was then added to this suspension. As benzaldehyde partial-
ly dissolves in water, an emulsion was formed and the si-
ACHTREUNGloxyACHTREUNGproline dissolved in the organic phase (Figure 2 center).
After the reaction mixture had been left to stand for 10 min,
the aqueous and oily phases were separated and the small
oily particles were left attached to the reaction vessel
(Figure 3 right). The oily particles were analyzed by 1H
NMR spectroscopy, which showed that they contained ben-
zaldehyde and cyclohexanone in a ratio of 1:2.2. This indi-
cates that benzaldehyde extracts some portion of the cyclo-
hexanone from the aqueous phase. Even though cyclohexa-
none is hydrophilic, benzaldehyde, highly hydrophobic si-
3 equiv of water
1
2
3
4
5
3
6
12
24
48
42
58
67
70
72
7.5:1
9.3:1
12:1
15:1
10:1
98
98
97
96
97
100 equiv of water
1
2
3
4
5
3
6
12
24
48
40
55
63
66
67
13:1
14:1
12:1
11:1
8:1
97
97
96
98
97
ACHTREUNGloxyACHTREUNGproline 7, and cyclohexanone, which is extracted from
the aqueous phase, form an organic phase, in which the
enantioselective aldol reaction proceeds. The reaction does
not proceed at the interface of the aqueous and organic
phases, in spite of the formation of an emulsion in some
cases. Thus, in this particular case, stirring is not necessary
even in the presence of a large amount of water.
[a] The reaction was performed by employing benzaldehyde (2.4 mmol),
cyclohexanone (4.8 mmol), and 7c (0.24 mmol), under neat reaction con-
ditions or in the presence of water (0.13 mL or 4.32 mL). [b] The com-
bined isolated yield of diastereomers. [c] Diastereoselectivity was deter-
mined by 1H NMR analysis of the reaction mixture. [d] Optical yield
refers to that of the anti isomer, which was determined by HPLC analysis
on a chiral phase.
Next we examined whether it is necessary for the siloxy
group and proline moiety to be combined in the same mole-
cule for the reaction to proceed efficiently. We attempted to
perform the aldol reaction of benzaldehyde and cyclohexa-
none in the presence of 100 equivalents of water using pro-
line (10 mol%) and tert-butyldiphenylsilanol (10 mol%)
[Eq. (1)]. Two phases were formed and no reaction proceed-
ed within two days. Thus, it is essential that the siloxy and
proline moieties be combined in the same molecule. It is
known that proline can promote the aldol reaction in an
aqueous polar organic solvent, in which case increasing the
water content decreases the enantioselectivity.[16] Introduc-
tion of the hydrophobic siloxy moiety into the catalyst cre-
ates a hydrophobic organic phase even in the presence of a
large amount of water, which is most probably the key to
the excellent reactivity and stereoselectivity.
Figure 3. Effect of water on the rate of the aldol reaction catalyzed by si-
loxyproline 7c.
Chem. Eur. J. 2007, 13, 10246 – 10256
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10251

Y. Hayashi et al.
selectivity were obtained from the beginning of the reaction,
and these selectivities did not change during its course. In
the presence of three equivalents of water, excellent enan-
tioselectivity was observed from the beginning of the reac-
tion. Though excellent diastereoselectivity was maintained
throughout, the diastereoselectivity initially increased and
then decreased from 24 h to 48 h. Thus, the retro-aldol reac-
tion proceeds to some extent, as we have reported for the
retro-aldol reaction of acetone and nitrobenzaldehyde cata-
lyzed by proline.[41] The present results indicate that there is
a degree of equilibrium between the starting materials and
the aldol product via the retro-aldol reaction, and that the
selectivity is mostly determined kinetically and not thermo-
dynamically.
In the presence of water, the stereoselectivity was excel-
lent compared to that obtained under neat reaction condi-
tions (Table 2). The reaction proceeds in the organic phase
in the presence of water, and these conditions are different
from reaction conditions such as a “concentrated organic
phase”.[28,29] Benzaldehyde, cyclohexanone, and the hydro-
phobic siloxyproline catalyst 7 form a hydrophobic organic
phase in which the enamine is generated, which then reacts
with the aldehyde even in the presence of a large amount of
water without any organic solvent. It is not clear at this
stage how one or more water molecules can act to improve
the stereoselectivity. We speculate that a small amount of
water dissolved in the organic phase affects the transition
state and that this improves the diastereo- and enantioselec-
tivities. This effect is small in energy and appears to be ef-
fective in the reactions of cyclic ketones, such as cyclohexa-
none and cyclopentanone, but not in the reactions of acyclic
ketones such as acetone or hydroxyacetone (vide infra).
Generality: The generality of the reaction was examined in
detail using 1 mol% of siloxyproline 7c and two equivalents
of ketone in the presence of three equivalents of water, as
well as under the conditions used in the previous paper, that
is, 10 mol% of the catalyst and five equivalents of ketone in
the presence of 18 equivalents of water (Table 6).[22] The re-
action has broad applicability with respect to the aldehyde.
Both excellent enantioselectivity (over 95% ee) and good
anti-selectivity were obtained when cyclohexanone and cy-
clopentanone were employed. Not only reactive, electron-
deficient aldehydes, but also aldehydes without an electron-
Table 6. Catalytic asymmetric aldol reactions in the presence of water catalyzed by siloxyproline 7c.[a]
Entry
Product
Amount of
catalyst [mol%]
Amount of
ketone [equiv]
Amount of
water [equiv]
Time [h]
Yield [%][b]
anti:syn[c]
Optical
purity
ACHTREUNG
[%ee][d]
1
2
10
1
5
2
18
3
18
48
78
73
13:1
10:1
>99
99
3
4
10
1
5
2
18
3
5
42
86
89
20:1
15:1
>99
97
5
6
10
1
5
2
18
3
28
42
80
90
20:1
17:1
97
99
7
8
10
1
5
2
18
3
50
136
21
24
4.7:1
4.0:1
96
94
9
10
10
1
5
2
18
3
40
42
89
96
19:1
12:1
97
98
11[e]
12
13
10
10
1
5
2
2
18
3
3
28
36
62
79
73
35
4.7:1
4.9:1
4.2:1
97
95
82
14
15
10
1
5
2
18
3
2.5
7
92
85
12:1
8.0:1
95
98
16
17
10
1
5
2
18
3
20
132
54
81
>20:1
>20:1
>99
98
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Siloxyproline-Catalyzed Aldol Reactions
Table 6. (Continued)
FULL PAPER
Entry
Product
Amount of
catalyst [mol%]
Amount of
ketone [equiv]
Amount of
water [equiv]
Time [h]
Yield [%][b]
anti:syn[c]
Optical
purity
ACHTREUNG
[%ee][d]
18
10
2
3
84
21
>20:1
96
19
20
21
10
10
1
5
2
2
18
3
3
24
45
152
76
63
40
>20:1
>20:1
>20:1
>99
99
99
22
10
2
3
84
29
>20:1
99
23[e]
24
10
1
5
2
18
3
18
42
74
76
9.0:1
10:1
>99
96
25
26
27
10
10
1
5
2
2
18
3
3
18
27
192
48
77
<10
>20:1
14:1
>20:1
95
95
84
28[f]
29[g]
30[g]
10
10
1
5
2
2
18
3
3
90
200
200
37
42
15
–
–
–
96
85
95
31[h]
32
33
10
1
1
2
2
2
3
3
0
96
120
120
51
79
15
–
–
–
57
68
65
34
35
36
10
10
1
5
2
2
18
3
3
72
150
150
61
65
<5
1:1
1:1.1
–
64, 61[i]
57
–
[a] The reaction was performed by employing an aldehyde (0.4 mmol), ketone (2 mmol), 7c (0.04 mmol), and water (0.13 mL) at room temperature, or
the reaction was performed by employing an aldehyde (2 mmol), ketone (4 mmol), 7c (0.02 mmol), and water (0.108 mL) at room temperature. [b] The
combined isolated yield of the diastereomers. [c] The diastereoselectivity was determined by 1H NMR analysis of the reaction mixture. [d] Optical yield
refers to that of the anti isomer, which was determined by HPLC analysis on a chiral phase. [e] Catalyst 7a was used instead of 7c. [f] Aqueous formalin
(35%, 0.035 mL, 0.4 mmol) and NaCl (47 mg) were employed. [g] Aqueous formalin (35%, 0.17 mL, 2.0 mmol) and NaCl (235 mg) were employed.
[h] Acetone (10.8 mmol) was employed. [i] Optical yield of the syn isomer.
withdrawing group proved to be excellent electrophilic part-
ners in this reaction. In the case of electron-rich aldehydes,
an excellent ee was obtained in spite of the low yield
(Table 6, entries 7 and 8). Though both aromatic and ali-
phatic aldehydes could be employed, the yield was moderate
or low with some of the aliphatic aldehydes, in which cases
excellent enantioselectivities were realized (Table 6, en-
tries 18 and 22). As regards heteroaromatic aldehydes, p-
pyridinecarbaldehyde gave excellent results (Table 6, en-
tries 14 and 15), but the reaction was slow in the case of fur-
fural. In this case, however, good results were obtained by
the use of 10 mol% of the catalyst (Table 6, entries 11–13).
2,2-Dimethyl-1,3-dioxan-5-one[37] can be successfully em-
ployed as the nucleophilic ketone, affording a polyoxy com-
pound with excellent selectivity. Here, the recommended
amount of catalyst is 10 mol%
organic phase and of five equivalents of ketone are recom-
mended (Table 6, entries 28–30).[10i,j,g,19a,38] However, this
method has its limitations. Though the aldol reactions of
acetone and hydroxyacetone proceeded in the presence of
water, the enantioselectivities were only moderate (Table 6,
entries 31–36). Cycloheptanone and cyclooctanone gave low
yields in their reactions with benzaldehyde under optimized
conditions.
In the reaction of unsymmetrical ketones such as 2-buta-
none, the reaction occurs preferentially at the methylene
carbon with good regiochemistry, affording the branched
aldol product with excellent enantioselectivity [Eq. (2)].
This regioselectivity[27b,d,42] is opposite to that of the reaction
performed in DMSO and catalyzed by proline.[16]
because the reaction is slow
with just 1 mol% ( Table 6, en-
tries 25–27).
A water-soluble
aldehyde such as formaldehyde
may be successfully employed,
though the use of NaCl as an
additive in order to aid extrac-
tion of formaldehyde into the
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10253

Y. Hayashi et al.
Large-scale preparation: Large-scale preparation of the
aldol was investigated. As the present direct aldol reaction
is atom-economical and does not generate by-products, and
only three equivalents of water are used without any organic
solvent, it should be possible to directly isolate the aldol
product. We investigated direct distillation of the reaction
mixture in cases when the aldol was liquid. If this were to
be successful, a series of tedious, routine procedures, such as
the addition of a quenching solution (e.g. buffer), extraction
using an organic solvent, drying of this organic phase with a
dehydrating reagent, then filtration and evaporation of the
organic solvent, would be eliminated. Direct distillation of
the reaction mixture, however, produced the aldol in 55%
yield with low anti-selectivity and low enantioselectivity
(89% ee). The yield and diastereo- and enantioselectivities
were lower than those of the original reaction, in which the
purification was performed by thin-layer chromatography.
These unsatisfactory results are ascribed to side reactions
such as the retro-aldol reaction, dehydration, and isomeriza-
tion, which take place when the reaction mixture is subject-
ed to high temperatures during distillation in the presence
of the catalyst. We envisaged that these side reactions might
be suppressed if the distillation were to be carried out in the
absence of the catalyst. After some experimentation, the fol-
lowing experimental procedure was established (Figure 4).
A reaction mixture of benzaldehyde (7.4 g, 1 equiv), cyclo-
hexanone (13.7 g, 2 equiv), catalyst 7c (259 mg, 1 mol%),
and water (3.8 mL, 3.0 equiv) was stirred at room tempera-
ture for 2 days. Silica gel (2.5 g) was then added to the reac-
tion mixture, subsequent filtration of which using ethyl ace-
tate (60 mL) gave an ethyl acetate solution. Distillation of
the filtrate produced the aldol product (10 g, 70%) with ex-
cellent diastereo- and enantioselectivities. Tedious proce-
dures such as extraction and drying of the organic phase
could thus be eliminated, and the total amount of organic
solvent employed to synthesize 10 g of the aldol product
was just 60 mL of ethyl acetate.
In the aldol reaction of p-nitrobenzaldehyde and cyclo-
hexanone, the product is solid and the following practical
large-scale procedure was developed. After stirring the reac-
tion mixture of p-nitrobenzaldehyde (10 g, 1 equiv), cyclo-
hexanone (13.7 mL, 2 equiv), catalyst 7c (245 mg, 1 mol%),
and water (3.6 mL, 3 equiv) at room temperature for 42 h, a
solid separated. This solid was collected by filtration using a
small amount of hexane (5 mL), during which process
excess cyclohexanone and the catalyst were removed be-
cause the catalyst dissolves in the excess cyclohexanone. The
solid was obtained in 80% yield, and consisted of the pure
aldol product as judged by 1H NMR spectroscopy
(400 MHz) with excellent diastereoselectivity (anti:syn
>20:1) and enantioselectivity (97% ee). A single recrystalli-
zation from iPrOH (21.5 mL) gave the nearly diastereomeri-
cally and enantiomerically pure aldol in 72% yield (anti:syn
>20:1, 99% ee). Only 26.5 mL of organic solvent was
needed to obtain 16.5 g of aldol.
No organic solvent is used in the reaction and only a
small amount is needed in the purification step. The re-
quired catalyst loading is 1 mol% and three equivalents of
safe and inexpensive water is employed as an additive. Thus,
these procedures constitute one of the most practical and
environmentally benign, green methods for the synthesis of
chiral aldol products. Reduction of the amount of ketone
and catalyst loading would be a challenging problem. An
ideal and even more environmentally benign process would
be one that does not require any organic solvent, not only in
the reaction but also in the purification steps. Recently, we
have accomplished such an organic solvent-free process in
the proline-catalyzed aldol reaction.[25]
Conclusion
We have developed highly hy-
drophobic trans-siloxy-l-pro-
line and cis-siloxy-d-proline
catalysts, both of which pro-
mote the direct asymmetric
aldol reaction of aldehydes and
ketones with excellent diaster-
eo- and enantioselectivities.
The reaction proceeds in the
organic phase, but water is es-
sential for the high selectivities.
As the reaction proceeds in
the presence of three equiva-
lents of water without any or-
ganic solvent, the large-scale
preparation, including the pu-
rification steps, of chiral aldols
with a minimal amount of or-
ganic waste becomes possible.
Figure 4. Large-scale performance of the aldol reaction of benzaldehyde and cyclohexanone catalyzed by
1 mol% of 7c.
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Siloxyproline-Catalyzed Aldol Reactions
FULL PAPER
Even in the presence of a large amount of water, an organic
phase is formed, and the enamine is generated and reacts
with the aldehyde in this phase, affording the aldol product.
As enamines are widely used in many kinds of organic reac-
tions,[43] other enamine-based reactions might also be per-
formed in the presence of a large amount of water.
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ACHTREUNG
(2S,1’R)-2-(Hydroxyphenylmethyl)cyclohexan-1-one[30g]: This is a known
compound. The absolute stereochemistry was determined by comparison
with the literature data.[30g]
[a]2D4 =+27.7 (c=0.85, CHCl3), >99% ee. Lit.: [a]2D4 =ꢁ24.2 (c=1.03,
CHCl3) (93% ee, (2R,1’S)-2-(hydroxyphenylmethyl)cyclohexanone).
Enantiomeric excess was determined by HPLC on a Chiralcel OD-H
column, l=213 nm, iPrOH/hexane, 1:100, 1.0 mLminꢁ1
(major), tr =25.9 min (minor).
; tr =19.4 min
Large-scale preparation of (2S,1’R)-2-(hydroxyphenylmethyl)cyclohexan-
1-one (used when the product is liquid): Catalyst 7c (259 mg, 0.74 mmol)
was added to a mixture of benzaldehyde (7.4 g, 74.4 mmol) and cyclohex-
anone (13.7 g, 149 mmol) in water (3.8 mL) at room temperature. The re-
action mixture was stirred for 48 h, then silica gel (2.5 g) was added. The
mixture was filtered through silica gel using ethyl acetate (60 mL), and
the crude organic materials were purified by distillation to afford 2-(hy-
droxyphenylmethyl)cyclohexan-1-one (10.0 g, 70%) as a colorless oil: an-
1
ti:syn=10:1 (by H NMR spectroscopy), >99% ee (by HPLC on a Chir-
alcel OD-H column, l=213 nm, iPrOH/hexane, 1:100, 1.0 mLminꢁ1; tr =
19.4 min (major), 25.9 min (minor)).
Large-scale preparation of (2S,1’R)-2-(hydroxy-p-nitrophenyl)methylcy-
clohexan-1-one (used when the product is solid): Cyclohexanone
(13.7 mL, 132 mmol) was added to a mixture of p-nitrobenzaldehyde
(10 g, 66.2 mmol), 7c (244 mg, 0.66 mmol), and water (3.6 mL) at room
temperature. After the reaction mixture had been stirred for 42 h at am-
bient temperature, a solid appeared and the mixture was filtered with
hexane (5.0 mL). The filtrate was concentrated to dryness, and the resi-
due was dried in vacuo and purified by recrystallization from isopropanol
(21.5 mL), which gave (2S,1’R)-2-(hydroxy-p-nitrophenylmethyl)cyclo-
hexan-1-one (11.9 g, 72%) as a colorless solid: anti:syn >20:1 (by 1H
NMR spectroscopy), 99% ee (by HPLC on a Chiralpak AS-H column,
l=254 nm, iPrOH/hexane, 1:10, 1.0 mLminꢁ1
; tr =11.2 min (major),
18.2 min (minor)).
Acknowledgements
This work was partially supported by the Toray Science Foundation, and
a Grant-in-Aid for Scientific Research from MEXT.
Chem. Eur. J. 2007, 13, 10246 – 10256
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: March 4, 2007
Revised: July 23, 2007
Published online: September 25, 2007
10256
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 10246 – 10256