Highly diastereo- and enantioselective direct aldol reactions in water

Article abstract of DOI:10.1002/anie.200502488

(Chemical Equation Presented) Going green: The synthetically very important aldol reaction can proceed in water without a metal catalyst with excellent enantioselectivity. The key to the reaction is a small, synthetic organic catalyst based on trans-hydroxyproline with a siloxy group. Thus, this method is an environmentally friendly process for the synthesis of chiral molecules.

Full text of DOI:10.1002/anie.200502488

Communications
Asymmetric Synthesis
DOI: 10.1002/anie.200502488
Highly Diastereo- and Enantioselective Direct
Aldol Reactions in Water**
Yujiro Hayashi,* Tatsunobu Sumiya, Junichi Takahashi,
Hiroaki Gotoh, Tatsuya Urushima, and Mitsuru Shoji
Reactions in which water is used as the solvent have attracted
a great deal of attention because water is an environmentally
friendly, safe medium, which avoids the problems of pollution
that are inherent with organic solvents.[1] The synthesis of
enantiopure molecules is another important issue, and the
development of enantioselective reactions in water is an
extensively investigated topic,[2] although it was long thought
to be mainly confined to the realm of enzymes. Successful
catalytic versions of enantioselective reactions have mostly
employed transition-metal complexes,[3] and may require
toxic, rare, and expensive metals, and suffer from possible
contamination of the products by metal. Organocatalysts,[4]
however, are free from these problems, and moreover are
inexpensive and stable to moisture and air. Thus, the
development of small organic molecules that catalyze enan-
tioselective reactions in water is currently a highly sought-
after goal in chemistry.
The aldol condensation is a key carbon–carbon bond-
forming reaction, which creates the b-hydroxy carbonyl
structural unit found in many natural products and drugs.[5]
In nature, type I and II aldolases catalyze this reaction in
water with perfect enantiocontrol through an enamine
mechanism and by using a zinc cofactor, respectively.[6] The
Mukaiyama aldol reaction proceeds in aqueous organic
solvent, but this is an indirect method that requires prefor-
mation of a silyl enol ether as a nucleophile.[7] A Zn-proline-
catalyzed aldol reaction occurs in aqueous media with
moderate enantiomeric excess.[8] However, proline can cata-
lyze direct aldol reactions in polar organic solvents with high
enantioselectivity,[4,9] but it affords the racemate in water.[10]
Although several chiral organocatalysts have been developed
for the aldol reaction,[4,11] and some of them provide aldols
enantioselectively in aqueous organic solvents,[12] they still
require the use of an organic solvent.[13] As far as we are
aware, only enzymes and antibodies of very high molecular
[*] Prof. Dr. Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima,
Dr. M. Shoji
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
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas 16073219 from The Ministry of
Education, Culture, Sports, Science, and Technology (MEXT).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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weight have been able to catalyze the direct aldol reaction in
water with high enantioselectivity.[5,6] Moreover, a rather
large catalyst loading is usually required for the aldol
reactions mediated by organocatalysts. Herein we describe a
synthetic small organic molecule that promotes highly
diastereo- and enantioselective aldol reactions in the presence
of water.
We have previously reported that 4-tert-butyldimethylsi-
loxyproline (1a), which is easily prepared from commercially
available trans-4-hydroxyproline, is a highly active proline
surrogate in the a-aminoxylation of carbonyl compounds and
the Mannich reaction.[14] Application of this siloxyproline as a
catalyst to the aldol reaction of cyclohexanone and benzal-
dehyde led to an unexpected result, namely, the asymmetric
aldol reaction proceeded efficiently in the presence of water
and the anti-aldol product was obtained with excellent
diastereoselectivity in a nearly optically pure form (Table 1,
isomer was obtained in good yield with excellent diastereo-
selectivity in a nearly optically pure form (entries 1, 6, and 7).
Although the amount of water had little effect on the yield
and selectivities, with the reaction proceeding in a two-phase
system, the reactions without a solvent or in an organic
solvent (DMSO)[17] resulted in lower enantioselectivity, with
formation of nearly equal amounts of anti and syn isomers
(entries 1–5). These results indicate that water is indispen-
sable for the high diastereo- and enantioselectivities.[18] The
reaction scarcely proceeded with the tetrazole catalyst 3 in the
presence of water; this catalyst, however, promoted the aldol
reaction of chloral in the presence of water (entry 10).[12a] As
proline (2) and hydroxyproline (1d) did not promote the
reaction in the presence of water, the siloxy group of catalyst 1
is clearly essential for the success of this reaction (entries 8,
9).
The generality of the reaction was examined in detail
using catalyst 1c, and the results are summarized in Table 2.
The reaction has broad applicability with respect to the
aldehyde: Both excellent enantioselectivity (over 95% ee)
and anti selectivity were obtained when cyclohexanone and
cyclopentanone were employed. Not only reactive, electron-
deficient aldehydes, but neutral aldehydes are also excellent
electrophilic partners in this reaction. Excellent ee values
were obtained in the case of electron-rich aldehydes, although
the yield was only moderate (entry 4). Both aromatic and
aliphatic aldehydes could be employed. Heteroaromatic
aldehydes such as furfural and para-pyridinecarbaldehyde
were also excellent substrates (entries 6 and 7). 2,2-Dimethyl-
1,3-dioxan-5-one can be employed successfully as the nucle-
ophilic ketone, and affords a polyoxy compound with
excellent selectivity (entry 11).[12f,19] Awater-soluble aldehyde
such as formaldehyde can also be employed successfully
(entry 12).[12a,d] The method has its limitations, however:
Although the aldol reaction of acetone and hydoxyacetone
proceeded in water, the enantioselectivity was moderate.
The effectiveness of the siloxyproline catalysts compared
to proline and hydroxyproline can be attributed to the
solubility of the catalysts. Although proline and hydroxypro-
line dissolve in water, siloxyproline is only partially soluble in
water and forms an organic phase with the aldehyde and
ketone in which the aldol reaction proceeds efficiently.
A preliminary study showed that the catalyst loading can
be reduced to as low as 1 mol% without compromising the
enantioselectivity, and 300 mol% of water is enough for the
reaction to be effected in a diastereo- and enantioselective
manner, although a longer reaction time is needed (2 days).
These reaction conditions are suitable for a preparative-scale
synthesis. After the reaction, filtration of the reaction mixture
through a short pad of silica gel removed the water and the
organocatalyst 1c, and only a small amount of extra solvent
was needed. The direct distillation of the filtrate afforded the
product in 78% yield with excellent enantioselectivity on a 6-
mmol scale [Eq. (1)].[20] It should be noted that this is the first
organocatalyst-mediated aldol reaction, in which only
1 mol% of organocatalyst can promote the reaction with
high diastereoselectivity and excellent enantioselectivity.
Our results show that the synthetic compounds 1 are the
first asymmetric organocatalysts that promote the aldol
Table 1: The effect of catalyst on the reaction yield and selectivity.[a]
Entry
Catalyst
Yield [%][b]
anti:syn[c]
ee [%][d]
1
1a
1a
1a
1a
1a
1b
1c
1d
2
61
66
69
61
65
71
78
<5
<5
<5
19:1
20:1
20:1
1.8:1
1:1
14:1
13:1
–
>99
>99
>99
89
2[e]
3[f]
4[g]
5[h]
6
80
>99
>99
–
7
8
9
10
–
–
–
–
3
[a] Unless otherwise shown, the reaction was performed with benzalde-
hyde (0.4 mmol), cyclohexanone (207 mL, 2.0 mmol), catalyst
(0.04 mmol), and H2O (0.13 mL) at room temperature for 18 h.
[b] Yield refers to the combined yield of isolated diastereomers.
[c] Diastereoselectivity was determined by 1H NMR analysis of the
reaction mixture. [d] Optical yield refers to that of the anti isomer and
was determined by HPLC analysis on a chiral phase (chiralcel OD-H).
[e] H2O (72 mL) was employed. [f] H2O (36 mL) was employed. [g] The
reaction was performed neat. [h] The reaction was performed in DMSO
(0.4 mL).
entry 1).[15] This is the first highly diastereoselective and
enantioselective aldol reaction carried out in the presence of
water without using an organic solvent. Screening the reaction
(Table 1) demonstrated that not only TBS-protected proline
1a (Scheme 1) but also TIPS- and TBDPS-protected prolines
1b and 1c[16] were excellent catalysts, and in all cases the anti
Scheme 1. Organocatalysts examined in this study. TBS=tert-butyldi-
methylsilyl, TIPS=triisopropylsilyl, TBDPS=tert-butyldiphenylsilyl.
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Communications
Table 2: The catalytic asymmetric aldol reaction in water catalyzed by siloxyproline 1c.[a]
Entry Product
1
t [h] Yield [%][b] anti:syn[c] ee [%][d] Entry Product
t [h] Yield [%][b] anti:syn[c] ee [%][d]
18
5
78
86
80
21
89
79
13:1
20:1
20:1
5:1
>99
>99
97
8
20
24
18
18
90
18
72
54
76
74
48
37
63
61
>20:1
>20:1
9:1
>99
>99
>99
95
2
9
3
28
50
40
28
10[e]
11
4
96
25:1
–
5
19:1
4.7:1
12:1
97
12[f]
13[g]
14
96
6[e]
97
–
67
7
2.5 92
95
1:1
64, 61[h]
[a] The reaction was performed with aldehyde (0.4 mmol), ketone (2.0 mmol), 1c (0.04 mmol), and H2O (0.13 mL) at room temperature.
1
[b] Combined yield of isolated diastereomers. [c] Diastereoselectivity was determined by H NMR analysis of the reaction mixture. [d] Optical yield
refers to that of the anti isomer and was determined by HPLC analysis on a chiral phase. [e] Catalyst 1a was used instead of 1c. [f] Aqueous formalin
(35%, 35 mL, 0.4 mmol) and NaCl (47 mg) were employed. [g] Acetone (10.8 mmol) was employed. [h] Optical yield of the syn isomer.
herein may open up a new avenue for the design of catalysts
that possess even better properties and are effective in water.
Experimental Section
Experimental procedure of Equation (1): Catalyst 1c (22.2 mg,
0.06 mmol) was added to a suspension of benzaldehyde (0.60 mL,
6.0 mmol), cyclohexanone (3.1 mL, 30 mmol), and water (0.32 mL,
18 mmol) at room temperature. The reaction mixture was stirred for
48 h, and silica gel (220 mg) was added to the reaction mixture. The
reaction in the presence of water without organic solvent, a
mixture was filtered through silica gel using ethyl acetate (10 mL),
process that has hitherto belonged to the realm of enzyme
chemistry. The reaction catalyzed by these siloxy catalysts has
the following notably features: 1) It proceeds in the presence
of water without organic solvent; 2) very high enantioselec-
tivity is attained in most cases; 3) both diastereo- and
enantioselectivities are higher than for the reaction per-
formed in an organic solvent; 4) the catalysts themselves can
be easily prepared in large quantities from trans-hydroxypro-
line, both enantiomers of which are commercially available;
5) a low catalyst loading (1 mol%) can be utilized. As the
synthetic catalysts can be easily modified, their selectivity and
reactivity may be tunable, and hence the findings reported
and the crude organic materials were purified by distillation to afford
2-(hydroxyphenylmethyl)cyclohexanone (954.3 mg, 78%) as a color-
less oil: anti:syn = 10:1 (by 1H NMR spectroscopy of the crude
mixture), > 99% ee (by HPLC on a chiralcel OD-H column, l =
213 nm, iPrOH/hexane 1:100, 1.0 mLminÀ1; tR = 19.4 min (major),
25.9 min (minor)).
Received: July 17, 2005
Published online: December 30, 2005
Keywords: aldol reaction · asymmetric synthesis ·
.
diastereoselectivity · organocatalysis · solvent effects
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[17] The other organic solvents gave poor results.
[18] In some reactions,[12] the ee value was increased in the presence
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[19] D. Enders, C. Grondal, Angew. Chem. 2005, 117, 1235; Angew.
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[20] The reaction could be also performed on a 70-mmol scale.
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