Green asymmetric synthesis: β-amino alcohol-catalyzed direct asymmetric aldol reactions in aqueous micelles

Article abstract of DOI:10.1002/chir.22120

The ability of chiral β-amino alcohols to catalyze the direct asymmetric aldol reaction was evaluated for the first time in aqueous micellar media. A family of cheap and easily accessible β-amino alcohols, obtained in one step from naturally occurring amino acids, was shown to successfully catalyze the asymmetric aldol reaction between a series of ketones and aromatic aldehydes. These aldol reactions furnished the corresponding β-hydroxy ketones with up to 93% isolated yield and 89% ee. (S)-2-phenylglycinol and Triton X-100 proved to be the best organocatalyst and surfactant, respectively. Copyright

Full text of DOI:10.1002/chir.22120

CHIRALITY 25:119–125 (2013)
Green Asymmetric Synthesis: b-Amino Alcohol-Catalyzed Direct
Asymmetric Aldol Reactions in Aqueous Micelles
2
1
AFRODITI PINAKA,1,2 GEORGIOS C. VOUGIOUKALAKIS,1,3 DIMITRA DIMOTIKALI, ELINA YANNAKOPOULOU,
*
1
BEZHAN CHANKVETADZE,4 AND KYRIAKOS PAPADOPOULOS
*
1Institute of Physical Chemistry, NCSR Demokritos, 15310 Athens, Greece
2Department of Chemical Engineering, NTU Athens, 15780 Athens, Greece
3Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Athens 15771, Greece
4Institute of Physical and Analytical Chemistry, School of Exact and Natural Sciences, Tbilisi State University, 0170 Tbilisi, Georgia
ABSTRACT
The ability of chiral b-amino alcohols to catalyze the direct asymmetric aldol
reaction was evaluated for the first time in aqueous micellar media. A family of cheap and easily
accessible b-amino alcohols, obtained in one step from naturally occurring amino acids, was shown
to successfully catalyze the asymmetric aldol reaction between a series of ketones and aromatic
aldehydes. These aldol reactions furnished the corresponding b-hydroxy ketones with up to 93%
isolated yield and 89% ee. (S)-2-phenylglycinol and Triton X-100 proved to be the best organocatalyst
and surfactant, respectively. Chirality 25:119–125, 2013. © 2012 Wiley Periodicals, Inc.
KEY WORDS: organocatalysis; asymmetric synthesis; aldol reactions; b-amino alcohols; surfactants
INTRODUCTION
sustainable development concerns and also seeking to cap-
italize on the easily accessible chiral pool of amino acids,
we decided to perform a detailed study on the catalytic
efficiency of chiral primary b-amino alcohols in the aldol
reaction of simple ketones with aromatic aldehydes in
aqueous micelles (Scheme 1).
Over the last decade, the direct asymmetric aldol reaction
has undergone a renaissance following the rebirth of organo-
catalysis.1–6 In nature, Class I aldolase enzymes efficiently
catalyze enantioselective aldol reactions in water via the
formation of enamine intermediates.7 These enzyme-catalyzed
reactions occur in a hydrophobic active site, where contacts
between bulk water and the reaction transition states can be
substantially diminished.8 From a green chemistry standpoint,
the development of organocatalysts that can mimic the aldolase
enamine mechanism, affording aldol products with high enan-
tioselectivities in an aqueous environment, is of great importance.
In 2000, List and coworkers reported that (S)-proline
efficiently catalyzes the intermolecular asymmetric aldol
reaction under mild conditions, through the formation of
enamine intermediates.9 Since then, there have been a great
number of reports on asymmetric aldol reactions catalyzed
by proline and proline derivatives, affording enantiopure
products in high yields.10–21 The first reports used organic
solvents, while, in most cases, the addition of water resulted in
a significant decrease in both reactivity and enantioselectivity.
More recently, however, a series of chiral proline-derived
organocatalysts were developed for the aldol reaction in
aqueous media. Some of these catalysts gave good yields and
excellent enantioselectivities.22–30 Only a small number of
nonproline-derived chiral organocatalysts for aqueous aldol
reactions have been reported to date.31–36
Although chiral primary b-amino alcohols are easily accessible
from inexpensive a-amino acids,37,38 there are only a handful of
reports regarding their application in organocatalytic asymmetric
aldol reactions thus far.30,39–44 In most of these studies, the
aldol reactions were performed in organic solvents.39–43 In only
two cases were chiral primary b-amino alcohols utilized to
catalyze direct aldol reactions in aqueous media, affording
poor-to-moderate results in terms of both reactivity and stereo-
selectivity.30,44 Moreover, to the best of our knowledge, there
are no reports on the catalytic efficiency of chiral primary
b-amino alcohols in aldol reactions performed in micellar
media. In this context, motivated by environmental and
© 2012 Wiley Periodicals, Inc.
EXPERIMENTAL
General Remarks
Reagents and solvents were purchased from commercial suppliers
and purified by standard techniques. For thin-layer chromatography
(TLC), compounds were visualized by irradiation with UV light and/
or by treatment with a solution of phosphor molybdic acid in ethanol
followed by heating. Flash column chromatography was carried out
on SiO2 (silica gel 60, 70–230 mesh ASTM). 1H-NMR and 13C-NMR
spectra were recorded on a 500-MHz (125-MHz for 13C) or a 250-MHz
(62.5-MHz for 13C) spectrometer at ambient temperature. Chiral high
performance liquid chromatography (HPLC) analyses were carried
out using Chiralpak AD-H, Lux Cellulose-2, Lux Cellulose-4, or Lux
Amylose-2 columns. Optical rotation measurements were performed
on a polarimeter and calculated from the equation [a]D = (a measured
100)/c  l; where l is the path length of cell and c the concentration of
the solution, which is given in g/100 ml. All reaction products were
isolated as chromatographically pure materials. Amino acids were
purchased from commercial suppliers and used without any further
purification. Cyclopentanone, cyclohexanone, cycloheptanone, acetone,
butan-2-one pentan-3-one, 4-nitrobenzaldehyde, 3-nitrobenzaldehyde,
and 4-cyanobenzaldehyde are all commercially available and were used
as received. b-Amino alcohol catalysts 4–9 were prepared according to
the literature.38
Additional Supporting Information may be found in the online version of this
article.
*Correspondence to: Georgios C. Vougioukalakis, Laboratory of Organic
Chemistry, Department of Chemistry, University of Athens, Athens 15771,
Greece. E-mail: vougiouk@chem.uoa.gr; Kyriakos Papadopoulos, Institute
of Physical Chemistry, NCSR Demokritos, 15310 Athens, Greece. E-mail:
kyriakos@chem.demokritos.gr
Received for publication 23 June 2012; Accepted 21 September 2012
DOI: 10.1002/chir.22120
Published online 28 November 2012 in Wiley Online Library
(wileyonlinelibrary.com).

120
PINAKA ET AL.
Scheme 1. Direct asymmetric aldol reaction between ketones and aromatic aldehydes catalyzed by b-amino alcohols in aqueous micellar media.
and ketone (20.0 mmol) in 50 ml of distilled water. After vigorous stirring of
the reaction mixture for 24 h at 60 ꢀC, the racemic product was extracted
with diethyl ether, dried over magnesium sulphate, and the organic solvents
evaporated under vacuum. The crude racemic aldol products were purified
by flash column chromatography (diethyl ether/petrol ether).
General Procedure for the Preparation of b-Amino Alcohol
Catalysts 4–938
In a three-necked, round-bottomed flask containing NaBH4 (2.28 g, 60
mmol) and 30 ml distilled THF, 15 mmol of the appropriate a-amino acid
were added and mechanically stirred under argon. The flask was
immersed in an ice-water bath, cooled down to 0 ꢀC and a solution of
concentrated sulfuric acid (1.5 ml, 28.6 mmol) diluted in 5.0 ml diethyl
ether was added in such a way that the reaction mixture temperature
was maintained below 20 ꢀC. The reaction mixture was then vigorously
stirred at room temperature under an argon atmosphere for approximately
20 h. After the completion of the reaction, 10 ml of an aqueous hydrochloric
acid solution (3 mole l-1) was added and the reaction mixture was mechani-
cally stirred vigorously for 2 h at room temperature. Subsequently, 15 ml of
an aqueous sodium hydroxide solution (5.0 mole l-1) were added and the
reaction mixture was vigorously stirred for 3 h at room temperature. Note
that the whole experimental procedure was performed inside a fume hood
in order to safely vent dangerous emissions (H2). The organic solvents of
the mixture were evaporated under vacuum and the remaining aqueous
solution was extracted with CHCl3 (3Â 50 ml). After drying, the organic
extracts over magnesium sulfate and evaporating the organic solvents, with
the aid of a rotary evaporator, b-amino alcohols 4–9 were obtained in pure
form after column chromatography (CHCl3/MeOH: 5/1). The purity of all
catalysts was verified by 1H- and 13C-NMR spectroscopy as well as by
comparison of their optical rotation values with those published in the
literature.37,45–50
HPLC Data of Chiral and Racemic Aldol Products 3a–h
Anti-(2S, 1’R)-2-[Hydroxy-(4-nitrophenyl)-methyl]-cyclopentanone
10,33,52
(3a).
HPLC (Lux Cellulose-4, n-hexane/isopropanol, 60:40, flow
rate: 1.0 ml/min, l = 254 nm): tR1(syn) = 6.82 min (2.09), tR1(syn) = 8.57 min
(3.58), ee (syn-product) = 26%; tR2(anti) = 11.54 min (166.30), tR2(anti) = 14.89 min
(59.73), ee (anti-product) = 47%; de = 94%.
Anti-(2S, 1’R)-2-[Hydroxy-(3-nitrophenyl)-methyl]-cyclopentanone
33,52
(3b).
HPLC (Lux Cellulose-2, n-hexane/isopropanol, 60:40, flow rate:
1.0 ml/min, l = 254 nm): tR1(syn) = 5.92 min (area 133.84), tR1(syn) = 7.25 min
(area 94.07) min, ee (syn-product) = 18%; tR2(anti) = 8.91 min (area 128.42),
tR2(anti) = 11.47 min (area 45.88), ee (anti-product)= 48%; de= 14%.
Anti-(2S, 1’R)-2-[Hydroxy-(4-cyanophenyl)-methyl]-cyclopentanone
52
(3c). HPLC (Lux Cellulose-4, n-hexane/isopropanol, 60:40, flow rate:
1.0 ml/min, l = 254 nm): tR1(syn) = 5.67 min (area 77.16), tR1(syn) = 6.85
min (area 65.50), ee (syn-product) = 8%; tR2(anti) = 9.60 min (area 241.33),
tR2(anti) = 14.06 min (area 92.33), ee (anti-product) = 44%; de = 40%.
Anti-(2R, 1’S)-2-[Hydroxy-(4-nitrophenyl)-methyl]-cyclohexanone
10,52
General Procedure for the Preparation of the Chiral Aldol
(3d).
HPLC
(Daicel
CHIRALPAK
AD-H,
n-hexane/
Products 3a–h30
isopropanol = 90:10, flow rate: 1.0 ml/min, l = 254 nm), tR1(syn)=18.62 min
(area 345.60), tR1(syn) = 21.80 min (area 121.92), ee (syn-product) = 48%; tR2
(anti) = 23.79 min (area 1198.48), tR2(anti) = 31.81 min (area 116.24), ee
(anti-product) = 82%; de = 48%.
To a mixture of a b-amino alcohol (1.0 mmol) in 10 ml of an aqueous
micellar solution (2.0 Â 10-2 mol l-1), TFA (78.0 ml, 1.0 mmol) was added at
room temperature. This reaction mixture was vigorously stirred for 10
min. The desired ketone (20.0 mmol) and aromatic aldehyde (5.0 mmol)
were then added and the reaction mixture was stirred for 48 h. The product
was extracted from the aqueous phase with diethyl ether (3Â 30 ml), dried
over magnesium sulfate, and the organic solvents were evaporated under
vacuum. Flash column chromatography purification (diethyl ether/petrol
ether) gave the corresponding aldol products as colorless solids or viscous
oils. The spectroscopic data of all aldol products were in agreement with
those reported in the literature.10,33,51 The syn/anti diastereoselectivity
was determined by 1H-NMR analysis of the crude aldol product or by HPLC
analysis after column chromatography purification. The enantiomeric
excess (ee) and the absolute configuration of the aldol products were
determined by chiral HPLC analysis and comparison of the measured
retention times with published data. The racemic products were obtained
using the ammonium fluoride method described below.
Anti-(2R, 1’S)-2-[Hydroxy-(3-nitrophenyl)-methyl]-cyclohexanone
10,33,52
(3e).
HPLC (Lux Amylose-2, n-hexane/isopropanol, 70:30, flow
rate: 1.0 ml/min, l = 254 nm): tR1(syn) = 8.68 min (area 10.47), tR1(syn) = 9.95
(area 33.19) min, ee (syn-product)= 52%; tR2(anti) = 12.79 min (area 10.60),
tR2(anti) = 15.52 min (area 180.4), ee (anti-product)= 89%; de= 62%.
Anti-(2S, 1’R)-2-[1-Hydroxy-1(4-cyanophenyl)-methyl]-cyclohexa-
52
none (3f). HPLC (Lux Cellulose-4, n-hexane/isopropanol, 60:40, flow
rate: 1.0 ml/min, l = 254 nm): tR1(syn) = 7.39 min (area 26.45), tR1(syn) = 9.00
(area 58.02) min, ee (syn-product)= 37%, tR2(anti) = 10.35 min (area 224.17),
tR2(anti) = 16.22 min (area 22.26), ee (anti-product)= 82%; de= 50%.
Anti-(2S, 1’R)-2-[Hydroxy-(4-nitrophenyl)-methyl]-cycloheptanone
33,52
General Procedure for the Preparation of the Racemic Aldol
(3g).
HPLC (Lux Cellulose-4, n-hexane/isopropanol, 90:10, flow rate:
Products 3a–h52
1.0 ml/min, l = 254 nm): tR1(syn) = 22.82 min (area 26.75), tR1(syn) = 24.75 min
(area 14.73), ee (syn-product) = 29%; tR2(anti) = 27.18 min (area 94.94),
A catalytic amount of NH4F (44.4 mg, 1.2 mmol, 30 mol %) was added to a
round-bottomed flask containing the desired aromatic aldehyde (4.0 mmol)
tR2(anti) = 32.93 min (area 71.45), ee (anti-product) = 14%; de = 60%.
Chirality DOI 10.1002/chir

b-AMINO ALCOHOL-CATALYZED ASYMMETRIC ALDOL REACTIONS IN AQUEOUS MICELLES
121
10,33
(4R)-4-Hydroxy-4-(4-nitrophenyl)-butan-2-one (3h).
HPLC
bromide (CTAB) and cetyltrimethylammonium chloride (CTAC)
led to negligible yields too. On the other hand, the anionic
surfactant sodium dodecyl sulphate (SDS) gave fairly good
yields, though the enantioselectivity was not satisfactory.
Additionally, the workup of the reaction proved to be a
difficult task, mainly due to the surfactant’s strong emul-
sifying properties. Utilization of nonionic surfactant Triton
X-100 delivered the best results in terms of both isolated
yield and stereoselectivity, in combination with a straight-
forward workup of the reaction mixture. During the course
of our experiments, we also observed that the addition of
a strong organic acid, such as trifluoroacetic acid (TFA),
resulted in a significant acceleration of the reaction.
Slightly inferior selectivities were obtained when TFA
was replaced by other organic, inorganic, or Lewis acids
such as boric acid, zinc chloride, or acetic acid (entry 8,
Table 1; entry 7, Table 3). It is also important to note that
while the organocatalytic aldol reactions between unmodi-
fied ketones and aldehydes are usually performed using
a large excess of the ketone,19,53 in the present work the
utilization of only four molar equivalents of cyclohexanone,
as well as the ketones that follow, was shown to be
adequate.
(Lux Amylose-2, n-hexane/ isopropanol, 70:30, flow rate: 1.0 ml/min,
l = 254 nm): tR1 = 7.91 min (S)-isomer (area 74.04); tR1 = 8.56 min (R)-
isomer (area 126.8), ee = 26%.
RESULTS AND DISCUSSION
To identify the most efficient micellar medium, we initially
performed the direct aldol reaction between cyclohexanone
(1b, Scheme 1) and 4-nitrobenzaldehyde (2a, Scheme 1),
catalyzed by (S)-phenylglycinol (4a, Figure 1), employing a
series of anionic, cationic, and non-ionic surfactants. The
results from these optimization experiments are summarized
in Table I. For comparison purposes, the same aldol reaction
was also performed in DMSO and THF, in bulk water, as well
as in neat conditions. When the reaction was carried out in
organic solvents, it resulted in very low yields or no aldol
product at all (entries 1–2, Table 1). Low yields were also
observed when bulk water or neat conditions were employed;
in this case, however, the isolated yields were satisfactory upon
employing a large excess of cyclohexanone (entries 3–4, Table 1).
The use of cationic surfactants cetyltrimethylammonium
With the optimum reaction medium and additive in hand,
that is, Triton X-100 aqueous micellar solutions in the presence
of TFA, we then evaluated the catalytic efficiency of a variety of
chiral primary b-amino alcohols (4–9, Figure 1) in the aldol
reaction between cyclohexanone (1b) and 4-nitrobenzaldehyde
(2a). Note that all b-aminoalcohols utilized were prepared in
one straightforward step from commercially available, inexpen-
sive chiral a-amino acids.37,38
The results from these studies are summarized in Table 2.
The best yield for the desired product 3d (93%) was obtained
when (S)-phenylalaninol (5) was used as catalyst (entry 3,
Table 2); however, the corresponding diasteroeselectivity
was very low. In terms of stereoselectivity, the best results
(82% ee, 48% de) were obtained when (S)-phenylglycinol
(4a) was utilized (entry 1, Table 2). (S, S)-isoleucinol (7)
and (S)-methioninol (8) afforded similar diastereoselectivity,
in relation to (S)-phenylglycinol, but their enantioselectivity
(ee < 65%) was lower (entries 5 and 6, respectively, Table 2).
In all cases the anti aldol product (3d) was produced in
Fig. 1. Primary b-amino alcohol organocatalysts (synthesized in one step
from a-amino acids) employed in this study.
TABLE 1. The direct asymmetric aldol reaction of cyclohexanone with p-nitrobenzaldehyde catalyzed by (S)-phenylglycinol (4a) in
various solvents and aqueous micellar solutionsa
Entry
Solvent/ Surfactant
Catalyst
Yieldb [%]
syn:antic [%]
ee (syn)/ ee (anti)c [%]
1
2
3
4
5
6
7
8
DMSO
4a
4a
4a
4a
4a
4a
4a
4a
--
22
89
97
Traces
46
--
50:50
49:51
No reaction
64/29
81/78
52/65
Not determined
50/38
THF
No solventd
Waterd
49:51
CTAC
SDS
Not determined
65:35
Triton X-100
43
48
26:74
31:69
48/82
39/81
Triton X-100e
aReaction conditions: (S)-phenylglycinol (1.0 mmol), additive (1.0 mmol), 1b (20.0 mmol), and 2a (5.0 mmol) in 10-mL aqueous micellar media (2.0 Â 10-2 mol L-1).
bIsolated yields (48-h reaction time) after purification by flash column chromatography.
cDiastereoselectivities and enantioselectivities were determined by chiral HPLC. The configuration of aldol products has been assigned by comparison to literature
data.30
dA 12-fold excess of cyclohexanone was employed.
eBoric acid instead of TFA was used as additive.
Chirality DOI 10.1002/chir

122
PINAKA ET AL.
TABLE 2. Screening of b-amino alcohol catalysts in the
asymmetric aldol reaction of cyclohexanone (1b) with 4-
nitrobenzaldehyde (2a) affording 3da
Yieldb
[%]
syn:antic
[%]
ee (syn)/ee (anti)c
Entry Catalyst
[%]
1
2
3
4
5
6
7
4a
4b
5
43
51
93
52
46
42
24
26:74
43:57
42:58
30:70
24:76
24:76
39:61
48/82
72/61
70/53
50/63
54/65
57/58
62/56
6
7
8
9
aReaction conditions: b-amino alcohol catalyst (1.0 mmol), TFA (1.0 mmol),
1b (20.0 mmol), and 2a (5.0 mmol) in 10 mL aqueous Triton X-100 solution
(2.0 Â 10-2 mol L-1).
bIsolated yields (48-h reaction time) after purification by flash column
chromatography.
cDiastereoselectivities and enantioselectivities were determined by chiral
HPLC. The configuration of aldol products has been assigned by comparison
to literature data.30
excess, having the absolute configuration (2S, 1’R).† As
expected, when (R)-phenylglycinol (4b) was used as catalyst,
an excess of the anti aldol product (3d) with the (2R, 1’S)
configuration was obtained.
Fig. 2. Aldol products 3a–h, obtained from (S)-phenylglycinol-catalyzed
direct asymmetric aldol reactions of ketones 1a–d with aromatic aldehydes
2a–c.
Encouraged by these results, we then studied the scope
and limitations of the (S)-phenylglycinol-catalyzed aldol
reactions in Triton X-100 aqueous micellar solutions (Figure 2;
Table 3). All reactions with cyclohexanone (1b) afforded the
corresponding aldol products 3d–f in good to high stereose-
lectivities (de = 44–62%, ee = 82–89%, entries 4–6, Table 3).
Especially with regards to enantioselectivity, the reaction
between cyclohexanone and 3-nitrobenzaldehyde gave the best
results (89%, entry 5, Table 3). The reaction of cyclohexanone
with 4-cyanobenzaldehyde (2f), in the presence of zinc chloride
as an additive, resulted in significantly lower enantioselectivity
for the major anti product (entry 7, Table 3). Aldol products
3a–c and 3g, obtained from cyclopentanone (1a) or
cycloheptanone (1c), were isolated with low-to-moderate
enantioselectivities for the major anti products (ee = 14–48%,
entries 1–3 and 8, Table 3). Nevertheless, the reaction of
cyclopentanone with 4-nitrobenzaldehyde gave the best results
in terms of diastereoselectivity (94%, entry 1, Table 3). It is worth
emphasizing that in almost all reactions the anti aldol products
were obtained in excess, with only two exceptions: i) in the
reaction of cyclopentanone (1a) with 3-nitrobenzaldehyde
(2b) (entry 2, Table 3); and ii) when SDS was utilized as surfac-
tant (entry 6, Table 1). Also note that all reactions recorded in
Tables 1–3 were stopped after 48 h, since prolonged reaction
times could lead to the racemization of the aldol products.
Finally, it turned out that when aliphatic ketones, such as
diethylketone, dipropylketone, acetophenone, propiophenone,
TABLE 3. (S)-Phenylglycinol-catalyzed direct asymmetric
aldol reactions of ketones 1a–d with aromatic aldehydes 2a–c
affording aldol products 3a–h in aqueous Triton X-100
solutionsa
Ketone/
aldehyde
Yieldb
[%]
syn:
ee (syn)/ ee
(anti)c [%]
Entry
Product
antic [%]
1
2
3
4
5
6
7
8
9
1a/2a
1a/2b
1a/2c
1b/2a
1b/2b
1b/2c
1b/2c
1c/2a
1d/2a
1d/2a
3a
3b
3c
3d
3e
3f
58
36
35
43
41
56
37
27
36
33
3:97
57:43
30:70
26:74
19:81
25:75
28:72
20:80
–
26/47
18/48
8/44
48/82
52/89
37/82
32/41
29/14
26
3fd
3g
3h
3he
10
–
27
aReaction conditions: (S)-phenylglycinol (1.0 mmol), TFA (1.0 mmol), 1a–d
(20.0 mmol), and 2a–c (5.0 mmol) in 10-mL aqueous Triton X-100 solution
(2.0 Â 10-2 mol L-1).
bIsolated yields (48-h reaction time) after purification by flash column
chromatography.
cDiastereoselectivities and enantioselectivities were determined by chiral
HPLC. The configuration of aldol products has been assigned by comparison
to literature data.30,54
† The configuration of aldol products has been assigned by comparison to
literature data. For example, the anti aldol product (2S, 1’R) produced in
excess appears on the HPLC chromatogram at about 10.6 min, while the
other anti enantiomer (2R, 1’S) appears at about 15.5 min (SI: Table 2,
entry 4). The syn enantiomers appear at about 8.2 and 9.1 min, respectively.
The diastereomeric excess was also determined by integrating the methine
proton attached directly to the hydroxyl-carbon (CHOH) at about 5.20
and 4.82 ppm in the corresponding 1H-NMR spectra, or the CHOH-carbon
in the 13C-NMR spectra at about 75 and 69 ppm for the syn and anti
diastereomers, respectively.
dZinc chloride was used as an additive.
eMyristic acid was used as an additive and surfactant.
and methylnaphthylketone, were employed as reagents, the
corresponding isolated yields were very low (results not shown
here), with the exception of acetone (1d) where isolated yields
ranging between 33% and 36% were obtained.
Chirality DOI 10.1002/chir

b-AMINO ALCOHOL-CATALYZED ASYMMETRIC ALDOL REACTIONS IN AQUEOUS MICELLES
123
A likely rationale for the materialization of asymmetric aldol
reactions in aqueous micellar media is that the amino alcohol
(the organocatalyst) and the acid (additive) self-assemble
with the reactants in the micellar interior via hydrophobic
interactions. The hydrophobic interior of these aqueous
micelles excludes water molecules from the aldol reaction
environment, resembling the enzyme-catalyzed aldol reactions
occurring in the corresponding hydrophobic enzymatic active
sites. In this concentrated micellar phase, the reaction proceeds
efficiently to afford the desired aldol products with moderate-
to-high enantioselectivity, which is most probably assisted
by hydrogen bonds between the enamine, the b-amino
alcohol, the acid, and the acceptor in the transition state
(vide infra). In analogy, aldol reactions carried out in water
by surfactant-like amphiphilic organocatalysts have been
proposed to take place in an emulsion rather than a biphasic
system.30
transition state are also presumed to play a key role in the
observed stereoselectivity, given that they lead to a more
rigid transition state.
CONCLUSIONS
In summary, we showed for the first time that chiral
primary b-amino alcohols, prepared in one step from readily
The proposed acid-assisted enamine mechanism for the
b-amino alcohol-catalyzed asymmetric aldol reaction reported
herein is shown in Scheme 2. The ketone initially reacts with
the protonated b-amino alcohol resulting in the formation of
an enamine, which, in the next step, reacts with the aromatic
aldehyde to give, after hydrolysis, the enantiomerically
enriched aldol products. The formation of anti product (2S,
1’R), when (S)-phenylglycinol is employed as a catalyst, is most
probably favored by the minimization of the steric hindrance in
the corresponding transition state. This diastereoselectivity
originates from a re- facial attack of the ketone-enamine
intermediate to the re- facial plane of the aldehyde (Scheme 3).
As expected, a si- facial attack of the ketone-enamine
intermediate to the si- facial plane of the aldehyde, leading
to the anti products (2R, 1’S) that were indeed observed, is
favored when (R)-phenylglycinol is utilized as a catalyst.
These hypotheses are in accordance with previously
proposed mechanistic rationalizations.19,55 Finally, as visual-
ized in Scheme 3, hydrogen bonds between the amine group
of the catalyst and the carbonyl group of the aldehyde in the
Scheme 3. Simplified schematic representation of the two possible
approaches of enamine-intermediates to aldehydes leading to anti (favored)
and syn (nonfavored) aldol products.
Scheme 2. Proposed mechanism for the b-amino alcohol-catalyzed direct asymmetric aldol reaction of cyclic and non cyclic ketones with aromatic aldehydes.
Chirality DOI 10.1002/chir

124
PINAKA ET AL.
19. For some recent examples, see: Mase N, Tanaka F, Barbas CF III. Synthesis
of b-hydroxyaldehydes with stereogenic quaternary carbon centers by direct
organocatalytic asymmetric aldol reactions. Angew Chem Int Ed
2004;43:2420–2423.
available and inexpensive a-amino acids, efficiently catalyze
the direct asymmetric aldol reaction of cyclic and noncyclic
unmodified ketones with aromatic aldehydes in aqueous
micellar solutions. The catalytic efficiency of these b-amino
alcohols, especially (S)-phenylglycinol, is enhanced by the
addition of TFA in catalytic amounts. This environmentally
benign reaction affords a series of aldol products in moderate-
to-high isolated yields and moderate-to-excellent diastereos-
electivities and enantioselectivities. The enantioselectivity
of the aldol products can be controlled through the selection
of the appropriate chiral amino alcohol catalyst. Further studies
focusing on the use of more complicated b-amino alcohol
catalysts are currently underway and will be reported in
due course.
20. Bellis E, Kokkotos G. 4-Substituted prolines as organocatalysts for aldol
reactions. Tetrahedron 2005;61:8669–8676.
21. Cobb AJA, Shaw DM, Longbottom DA, Gold JB, Ley SV. Organocata-
lysis with proline derivatives: improved catalysts for the asymmetric
Mannich, nitro-Michael and aldol reactions. Org Biomol Chem
2005;3:84–96.
22. Peng Y-Y, Qiu-Ping D, Li Z, Wang PG, Cheng J-P. Proline catalyzed aldol
reactions in aqueous micelles: an environmentally friendly reaction
system. Tetrahedron Lett 2003;44:3871–3875.
23. Hayashi Y, Sumiya T, Takahashi J, Gotoh H, Urushima T, Shoji M. Highly
diastereo- and enantioselective direct aldol reactions in water. Angew
Chem Int Ed 2006;45:958–961.
24. Mase N, Watanabe K, Yoda H, Takabe K, Tanaka F, Barbas CF III.
Organocatalytic direct Michael reaction of ketones and aldehydes with
b-nitrostyrene in brine. J Am Chem Soc 2006;128:4966–4967.
ACKNOWLEDGMENTS
The authors thank NCSR Demokritos and the National Technical
University of Athens for financial support. A.P. is grateful to
NCSR Demokritos for a PhD fellowship. The Foundation
for Education and European Culture is acknowledged for
providing a scholarship to G.C.V.
25. Brogan AP, Dickerson TJ, Janda KD. Enamine-based aldol organocatalysis
in water: are they really “all wet”? Angew Chem Int Ed 2006;45:8100–8102.
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27. Vishnu M, Raj M, Singh VK. Highly enantioselective organocatalytic
direct aldol reaction in an aqueous medium. Org Lett 2007;9:2593–2595.
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