Highly efficient asymmetric direct stoichiometric aldol reactions on/in water

Article abstract of DOI:10.1002/anie.200703606

(Figure Presented) Hydrophobic pocket pleaser: A novel asymmetric catalytic system in water mediated by sulfated β-cyclodextrin (see picture) can bind the organocatalyst tert-butylphenoxyproline and associated hydrophobic reactants. Enantio- and diastereoselectivities up to >99% and close to quantitative yields could be achieved for stoichiometric direct aldol reactions of cyclohexanone and aryl aldehydes with this system.

Full text of DOI:10.1002/anie.200703606

Angewandte
Chemie
DOI: 10.1002/anie.200703606
Asymmetric Synthesis
Highly Efficient Asymmetric Direct Stoichiometric Aldol Reactions
on/in Water**
Junmin Huang, Xiaotong Zhang, and Daniel W. Armstrong*
Many enzymes catalyze reactions in water under mild
conditions with high efficiency and excellent stereoselectivity.
This highly effective and environmentally benign synthetic
methodology is often regarded as a goal in modern organic
chemistry.[1] Although enzymes have synthetic utility, they are
usually limited by their lack of large-scale compatibility.[2] It is
highly desirable to develop a chemical system that can mimic
the action of enzymes and effect organic reactions in water
with excellent efficiency and stereoselectivity. Water can be a
safe, inexpensive, and environmentally friendly solvent, which
makes its use favorable both in academic laboratories and in
industry. The pioneering studies of Diels–Alder reactions in
water by Breslow[3] in the early 1980s triggered a more
widespread interest in the use of water as a medium for
organic synthesis, not only because these reactions eliminate
the necessity of vigorously drying solvents and substrates, but
also because of the unique reactivity and selectivity often
observed in aqueous reactions. In the past two decades
considerable effort has been made in developing water-based
synthetic organic reactions.[4] Thus far, only a relatively
limited number of enantioselective organic reactions can be
carried out effectively in this solvent and the associated
mechanisms can be unclear.[5] Indeed, it appears that asym-
metric synthesis in water is still not a routine or preferred
procedure.
Enantioselective metal catalysis has revolutionized asym-
metric synthesis over the past 20 years and was recognized by
the 2001 Nobel Prize in Chemistry.[6] Subsequently, the
seminal work by List, Lerner, and Barbas on the intermo-
lecular adaptation of the proline-catalyzed direct asymmetric
aldol reaction[7] has focused attention on the catalytic
asymmetric reaction by metal-free small organic molecules
(organocatalysts). This synthetic approach has received much
attention in light of its green chemistry advantages.[8] Proline
is regarded as an effective and versatile small-molecule
“enzyme”[9] that catalyzes a wide range of organic trans-
formations. However, unlike enzymatic reactions in nature
that occur in water, enantioselective organocatalytic process-
es have typically been carried out in organic solvents. For
example, proline-catalyzed aldol reactions[10] can only afford
high enantioselectivity in solvents such as dimethylsulfoxide
(DMSO) and N,N-dimethylformamide (DMF). The presence
of a large amount of water has typically resulted in the
formation of products with low or no enantioselectivity.[11]
DMSO or DMF as solvents make the proline-catalyzed
reaction workup and catalyst recycling difficult. In nature,
aldolase enzymes catalyze the direct aldol reaction in water
with excellent stereocontrol the reaction proceeds in a
hydrophobic pocket to diminish contacts between bulk
water and the reaction transition state.[8f] We therefore
wanted to expand the concept of a hydrophobic pocket in
water for the asymmetric assembly of direct aldol reactions
under environmentally benign conditions.
The field of enantioselective organocatalysis in water
afforded further unsatisfactory results[11–14] until recently
when breakthrough contributions were made by the groups
of Barbas[15b,c] Takabe,[15b,c] and Hayashi.[15d,e] They used
proline-derived catalysts in the presence of water to demon-
strate the direct asymmetric aldol reaction and the Michael
reaction with high yields and with excellent diastereoselec-
tivities and enantioselectivities. Thereafter, many organo-
catalysts have been designed for the direct aldol reaction and
other reactions in aqueous conditions on the basis of the so-
called “enamine catalysis”, a process that mimics type I
aldolases.[15,16] It should be noted that with all of the organo-
catalysts and reaction conditions, a large excess of ketone is
employed. When an expensive ketone is used in large excess,
it is not reassuring for the direct aldol reaction with atom-
economical “green” credentials. In particular, the use of less-
volatile ketones in large excess, for example, cyclohexanone
(b.p. 1558C), complicates the reaction workup and product
purification.[13f] A highly efficient, stereoselective, and atom-
economical reaction in water is currently a sought-after goal
in chemistry.[17] Herein, we describe a tert-butylphenoxypro-
line (4)/cyclodextrin system (Figure 1) for highly efficient
asymmetric synthesis in water. We envision that cyclodextrins
mimic enzymes to form a hydrophobic pocket in water,[17f]
which can concentrate the organocatalyst and reactants,
assemble substrates, diminish contacts between bulk water
[*] Dr. J. Huang, X. Zhang, Prof. Dr. D. W. Armstrong
Department of Chemistry and Biochemistry
The University of Texas at Arlington
Arlington, Texas 76013 (USA)
Fax: ( +1)817-272-0619
E-mail: sec4dwa@uta.edu
[**] We gratefully acknowledge the Robert A. Welch Foundation Y-0026
for the support of this work.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Figure 1. The asymmetric catalytic system in water mediated by water-
soluble b-cyclodextrins.
Angew. Chem. Int. Ed. 2007, 46, 9073 –9077
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
and the reaction transition states, and thus alter the reaction
reactants of cyclohexanone and benzaldehyde. Under the
same conditions, catalyst 2 with a hydrophobic tert-butyl
group was not effective, and a low conversion (8% yield) was
observed (Table 1, entry 3). However, encouraged by the
excellent enantioselectivity achieved with catalyst 2 (98% ee
for the anti isomer), we investigated catalyst 4, which has an
even more hydrophobic tert-butylphenyl moiety, and it
exhibited greatly improved catalysis “on water”[19] (Table 1,
entries 5 and 7). The organocatalyst 4 is not soluble in water,
because of the highly hydrophobic tert-butylphenyl moiety.
The role of water is to bring the hydrophobic catalyst and
reactants closer together, and to form tiny “oil” droplets
floating on water during the vigorous stirring of the reaction
mixture. We reasoned that the association of 4 with hydro-
phobic reactants in the tiny “oil” droplets was required to
carry out the reaction on water, so that bulk water was largely
excluded from the reaction transition states. This reaction
afforded the aldol products in good yield and with high
stereoselectivity. When the same volume of cyclohexanone
was used to replace water as the solvent to produce a
homogeneous phase (Table 1, entries 7 and 9), the reaction
slowed down remarkably, and a significant drop in both
diastereoselectivity and enantioselectivity was observed. In
the solvent-free stoichiometric reaction, a comparable yield
was achieved for the aldol product but with significantly
decreased enantioselectivity and diastereoselectivity relative
to the same reaction on water (compare Table 2, entry 1 and
Table 1, entry 7). It seemed that the concentration of organo-
catalyst determined the reaction rate and that a large excess
mechanism and stereochemistry. Initial focus is on the atom-
economical aldol reaction using stoichiometric amounts of
cyclohexanone and various aryl aldehydes.
The catalytic activities of 1–4 for the asymmetric direct
aldol reaction were investigated by performing a model
reaction using stoichiometric amounts of benzaldehyde and
cyclohexanone, and the results are summarized in Table 1.
List and co-workers reported that the reaction of benzalde-
hyde in DMSO/cyclohexanone (4:1 v/v) catalyzed by proline
Table 1: Screening of organocatalysts for the direct aldol reaction of
cyclohexanone with benzaldehyde on water.[a]
Entry
Catalyst
Yield [%][b]
anti/syn[c]
ee [%][c]
1
1
1
2
3
0
67
8
Table 2: Effect of water on the solvent-free reaction of cyclohexanone
with benzaldehyde catalyzed by 4a.[a]
2[d]
3
70:30
87:13
68
98
Entry
H2O [mol%]
Yield [%][b]
anti/syn[c]
ee [%][c]
4
0
5
4b
4b
4a
4a
4a
4a
4a
4a
70
59
78
48
46
82
82
82
93:7
87
81
92
59
64
91
92
98
1
2
3
4
5
0
50
100
200
300
85
84
84
84
83
69:31
89:11
90:10
90:10
89:11
61
94
91
94
93
6[d]
7
74:26
90:10
78:22
67:33
84:16
83:17
87:13
8[d]
9[e]
10[f]
11[g]
12[h]
[a] Reaction conditions: benzaldehyde (5.0 mmol), cyclohexanone
(5.0 mmol), 4a (2 mol%, 0.1 mmol), and various amounts of added
water, at room temperature for 48 h. [b] Combined yield of isolated
diastereomers. [c] Determined by 1H NMR spectroscopy and HPLC on a
chiral stationary phase.
[a] Reaction conditions: benzaldehyde (5.0 mmol), cyclohexanone
(5.0 mmol), catalyst (2 mol%, 0.1 mmol), and water (2.0 mL), at room
temperature for 48 h. [b] Combined yield of isolated diastereomers. [c]
1
Determined by H NMR spectroscopy and HPLC on a chiral stationary
phase. [d] 2.0 mL of [BMIM]+[NTf2]À used as solvent. [e] 2.0 mL of
cyclohexanone used as solvent. [f] 2.0 mL of saturated brine used as
solvent. [g] 2.0 mL of aqueous lithium chloride solution (200 mol% LiCl)
used as solvent. [h] 2.0 mL of aqueous guanidine hydrochloride solution
(200 mol% NH2C(NH)NH2·HCl) used as solvent.
of ketone was not advisable for the direct aldol reaction as it
decreased the yield. When the reaction was conducted on
water, both the enantio-and diastereoselectivities increased
greatly, thus indicating that water participated in the reaction
transition states through hydrogen bonding and enhanced the
stereoselectivity of the reaction.[19c] The stoichiometric aldol
reaction was significantly improved after only 50 mol% water
was introduced; the corresponding product was obtained in a
good yield with both high diastereoselectivity and enantiose-
lectivity (Table 2, entries 1 and 2). Further addition of water
(up to 300 mol% or in a large volume of water, Table 2,
entries 2–5 and Table 1, entry 7) did not decrease the yield or
stereoselectivity. The carboxylic acid function seemed to be
important for the asymmetric catalysis, as the hydrophobic
(30 mol%) at room temperature for 4 days afforded the aldol
product in 85% yield with no diastereoselectivity and
moderate enantioselectivity (85% ee for the anti isomers
and 76% ee for the syn isomers).[18] When water was used to
replace the organic solvent (DMSO), no reaction progress
was detected after 2 days for the stoichiometric reaction
(Table 1, entry 1), probably because proline is dissolved in the
water phase and thereby separated from the hydrophobic
9074 www.angewandte.org
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Angew. Chem. Int. Ed. 2007, 46, 9073 –9077
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Angewandte
Chemie
catalyst 3 did not afford any products on water (Table 1,
entry 4). Switching to the ionic liquid [BMIM]+[NTf2]À as
solvent (Table 1, entries 2, 6, and 8) made the reaction a
homogeneous phase, but did not lead to either good yield or
4-tert-butylphenol in water with an association constant of
3.6 ” 104 mÀ1 [22]
The strong inclusion complex is hydrophobic
.
and results from the association of the tert-butylphenyl moiety
with the hydrophobic cavity of b-CD. Therefore, 4 may
strongly bind sulfated b-CD in water and generate the
enamine intermediate and transition states in situ from
reactants in the hydrophobic pocket formed by the CD. In
the above reactions, only 10 mol% of sulfated b-CD was
applied as an inverse phase-transfer reagent, and the reaction
system was not homogeneous, but rather formed two phases.
The question arises: Does the aldol reaction occur in the tiny
“oil” phase on water, in the cavities formed by the CDs in
water, or both? To address this question, the exact location of
catalyst 4 must be determined. We examined the water
solubility of 4 by adding 13.2 mg of 4a (0.05 mmol) to 2 mL of
D2O, which produced a suspension. After 0.10 mmol of
sodium sulfated b-CD was added to the mixture, it formed a
clear homogeneous solution. The partitioning of 4a between
organic solvents and water was examined by extraction of the
stereoselectivity
(BMIM = 1-butyl-3-methyimidazolium,
NTf2 = bis(trifluoromethylsulfonyl)imide). Salt effects on
the reaction were investigated (Table 1, entries 10–12), and
a remarkably high ee value was achieved in the aqueous
guanidine hydrochloride solution (98% ee for the anti
isomer).
Encouraged by the excellent enantioselectivity achieved
with the “salt-in” effect of guanidine hydrochloride (Table 1,
entry 12), we used surfactants to generate micelles to
associate the hydrophobic organocatalyst and reactants in
water. Excellent diastereoselectivity and enantioselectivity
were achieved in water mediated by different types of
surfactants (Table 3, entries 1–3). However, the applicability
of the method is limited by the problematic workup of the
emulsified reactions, as separation of the aqueous and organic
phases is difficult.[20]
1
above solution with 2 mL of CDCl3. H NMR spectroscopic
analysis of both CDCl3 and D2O phases demonstrated that
there was no detectable 4a in the CDCl3 organic phase. It is
concluded that the aldol reaction occurred in the water phase
where organocatalyst 4 resided with sulfated b-CD. Further-
more, a homogeneous reaction was achieved using 300 mol%
of sulfated b-CD to transfer all of the organocatalyst and
reactants in a large amount of water. This reaction exhibited
excellent enantioselectivity and high diastereoselectivity but a
low yield (Table 3, entry 7). The yield obtained in this
homogeneous aldol reaction was low because the catalyst
and reactants were sequestered in separate CDs and were
diluted in water.
A series of aldehydes was evaluated to examine the scope
of aldol reactions using this asymmetric catalytic system in
water (Table 4). The sulfated b-CD acted only as an inverse
phase-transfer reagent. It could not catalyze the aldol reaction
(Table 4, entry 3) without binding with 4a, which generated
the enamine intermediate with the ketone and attacked the
Table 3: The direct aldol reaction of cyclohexanone with benzaldehyde in
water mediated by surfactants and cyclodextrin.[a]
Entry
Catalyst
Yield [%][b]
anti/syn[c]
ee [%][c]
1[d]
2[e]
3[f]
4[g]
5[g]
6[g]
7[h]
4a
4a
4a
4b
1
17
67
72
70
0
92:8
91:9
93:7
93:7
99
98
98
94
4a
4a
78
15
90:10
90:10
96
98
[a] Reaction conditions: benzaldehyde (5.0 mmol), cyclohexanone
(5.0 mmol), catalyst (2 mol%, 0.1 mmol), surfactant (20 mol%) or
sulfated b-cyclodextrin (10 mol%), and water (2.0 mL), at room temper-
ature for 48 h. [b] Combined yield of isolated diastereomers. [c] Deter-
mined by 1H NMR spectroscopy and HPLC on a chiral stationary phase.
[d] Mediated by the anion-type surfactant sodium dodecyl sulfate.
[e] Mediated by the cation-type surfactant hexadecyltrimethyl ammoni-
um bromide. [f] Mediated by the zwitterion-type surfactant N-dodecyl-
N,N-dimethyl-3-ammonio-1-propanesulfonate. [g] Mediated by sodium
sulfated b-cyclodextrin. [h] Homogeneous reaction: cyclohexanone
(0.5 mmol), benzaldehyde (0.5 mmol), 4a (20 mol%, 0.1 mmol), sul-
fated b-cyclodextrin (300 mol%), and water (5.0 mL), at room temper-
ature for 48 h.
Table 4: The asymmetric aldol reactions of cyclohexanone with various
aryl aldehydes in water mediated by cyclodextrin.[a]
Entry Aryl aldehyde
Yield [%][b] anti/syn[c] ee [%][c]
1
2
benzaldehyde
78
97
0
97
100
80
92
90:10
>99:1
96
>99
2-nitrobenzaldehyde
2-nitrobenzaldehyde
3-nitrobenzaldehyde
4-nitrobenzaldehyde
4-chlorobenzaldehyde
4-bromobenzaldehyde
It is well-documented that cyclodextrin (CD) can act as an
inverse phase-transfer catalyst to allow water-insoluble mol-
ecules to react in an aqueous medium.[21] Although the
hydrophobic reactants benzaldehyde and cyclohexanone
could be transferred into the water phase by sulfated b-CD,
no product was detected from the aldol reaction using l-
proline as the catalyst (Table 3, entry 5), because the reactants
were kept in the hydrophobic cavities of the CDs and were
separated from the l-proline catalyst, which resided in water.
To our delight, stoichiometric amounts of cyclohexanone and
benzaldehyde were catalyzed by 4 using sulfated b-CD as an
inverse phase-transfer reagent in water and afforded the aldol
product in good yields and with both high enantioselectivity
and diastereoselectivity (Table 3, entries 4 and 6). b-CD binds
3[d]
4
96:4
96:4
95:5
93:7
94:6
88:12
92:8
84:16
>99
>99
99
99
>99
98
5
6
7
8
9
10
11
4-trifluoromethylbenzaldehyde 100
4-methylbenzaldehyde
2-methylbenzaldehyde
2-furaldehyde
65
62
71
96
98
[a] Reaction conditions: aryl aldehyde (5.0 mmol), cyclohexanone
(5.0 mmol), 4a (2 mol%, 0.1 mmol), sulfated b-cyclodextrin
(10 mol%), and water (2.0 mL), at room temperature for 48 h.
[b] Combined yield of isolated diastereomers. [c] Determined by
1H NMR spectroscopy and HPLC on a chiral stationary phase. [d] With-
out catalyst 4a.
Angew. Chem. Int. Ed. 2007, 46, 9073 –9077
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
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the electronic nature of the aromatic aldehydes, excellent
stereoselectivities were obtained. After the reaction was
complete, the products were obtained by simple filtration or
phase separation. No trace of organocatalyst 4a could be
detected in the products by 1H NMR spectroscopy, thus
indicating that tert-butylphenoxyproline 4 was trapped by
sulfated b-CD in the water phase. Notably, the extremely high
stereoselectivity (> 99% enantioselectivity and > 99% dia-
stereoselectivity) and almost quantitative yield were achieved
in stoichiometric aldol reactions of cyclohexanone and strong
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electron-withdrawing aromatic aldehydes with
a small
amount of catalyst 4a (2 mol%).
In conclusion, we have developed an asymmetric catalytic
system in water mediated by sulfated b-CD which can bind an
organocatalyst of tert-butylphenoxyproline and associated
hydrophobic reactants. This system demonstrates up to
> 99% enantioselectivity and > 99% diastereoselectivity
and near quantitative yields for stoichiometric direct aldol
reactions of cyclohexanone and aryl aldehydes. When the
strong electron-withdrawing substituted aryl aldehydes were
subjected to the asymmetric catalytic system, simple filtration
or phase separation afforded the highly enantiopure aldol
products in near quantitative yields. Additional studies to
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Experimental Section
The general procedure for the aldol reaction in water mediated by
sulfated b-cyclodextrin: Cyclohexanone (0.52 mL, 5 mmol) and aryl
aldehyde (5 mmol) were added to a solution of organocatalyst
(2 mol%, 0.1 mmol) and sulfated b-cyclodextrin (10 mol%) in water
(2.0 mL), and the reaction mixture was stirred at room temperature
for 48 h. Filtration or liquid phase separation afforded the crude
product, which was either pure or further purified by silica gel flash
chromatography (hexanes/EtOAc). The anti/syn ratio (diastereose-
lectivity) and ee values (enantioselectivity) were determined by
1H NMR spectroscopy and HPLC on a chiral stationary phase.
HPLC conditions: Chiralpak IB (15 cm ” 4.6 mm, Chiral Technolo-
gies, Inc.), 1% v/v iPrOH in heptane as mobile phase, 1 mLminÀ1
flow rate, 213 nm UV detector.
Received: August 7, 2007
Published online: October 24, 2007
Keywords: aldol reaction · asymmetric synthesis · cyclodextrins ·
.
organocatalysts · water
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