Highly enantioselective asymmetric direct aldol reaction catalyzed by amine-functionalized tridentate sulfinyl ligands

Article abstract of DOI:10.1016/j.tetasy.2011.07.008

Enantiomerically pure, diastereomeric tridentate ligands bearing hydroxyl, sulfinyl, and amino moieties as nucleophiles have proven to be highly efficient catalysts in the enantioselective asymmetric direct aldol reaction giving the desired products in very high yields (up to 98%) and with ee's of up to 97%. The influence of the stereogenic centers located on the sulfinyl sulfur atom, and on the amino moiety, on the stereochemical course of the reaction is also discussed.

Full text of DOI:10.1016/j.tetasy.2011.07.008

Tetrahedron: Asymmetry 22 (2011) 1325–1327
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective asymmetric direct aldol reaction catalyzed
by amine-functionalized tridentate sulfinyl ligands
Michał Rachwalski a, , Stanisław Lesniak , Piotr Kiełbasinski
⇑
a
b
´
´
a
´
´
Department of Organic and Applied Chemistry, University of Łódz, Tamka 12, 91-403 Łódz, Poland
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Łódz, Poland
b
´
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure, diastereomeric tridentate ligands bearing hydroxyl, sulfinyl, and amino moieties
as nucleophiles have proven to be highly efficient catalysts in the enantioselective asymmetric direct
aldol reaction giving the desired products in very high yields (up to 98%) and with ee’s of up to 97%.
The influence of the stereogenic centers located on the sulfinyl sulfur atom, and on the amino moiety,
on the stereochemical course of the reaction is also discussed.
Received 23 May 2011
Accepted 12 July 2011
Available online 10 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The direct aldol reaction constitutes a fundamental C–C bond
forming reaction in organic chemistry.1,2 Its enantioselective ver-
sion has become a very important tool for asymmetric synthesis.
This transformation relies on the carbonyl compound acting as a
nucleophile by itself or with another carbonyl group (electrophile)
to give the appropriate product of a condensation (aldol).1 There
are many examples in the literature which describe the enantiose-
lective direct aldol reaction catalyzed by proline,3–6 its deriva-
2.1. Screening of the ligands
Seven chiral tridentate catalysts, containing aziridines 1a–d,
(ꢀ)-(S)- and (+)-(R)-1-phenylethylamine 1e,f and (ꢀ)-(S)-1-(10-
naphthyl)-ethylamine 1g were tested, since each of them proved
to be efficient as a catalyst for the aforementioned reactions
(Scheme 1).
To check the catalytic activity of these ligands in the enantiose-
lective direct aldol reaction, we chose the condensation of acetone
with benzaldehyde as a reference transformation. The reactions
were performed at room temperature in acetone and no additional
solvent was used (Scheme 2). The results are shown in Table 1.
The results of Table 1 show that the stereogenic sulfinyl group
exerts moderate asymmetric induction. This is visible in the case
of catalyst 1a bearing an achiral aziridine moiety (entry 1), in
which the sulfinyl group is the only source of chirality. Ligands
bearing chiral acyclic amines 1e–g proved to be much more
efficient catalysts (entries 5–7) than those obtained from chiral
aziridines 1b,c,d (entries 2, 3, and 4). Interestingly, a similar rela-
tionship was found in the Henry and aza-Henry reactions.16,17
Moreover, the decisive role in stereocontrol of the aldol reaction
was caused by the stereogenic centers located in the amine moie-
ties; the effect, which was again the same as in the case of the
Henry and aza-Henry reactions. This can be seen in entries 2 and
3, and 5 and 6 where the use of diastereomeric catalysts 1b and
1c, and 1e and 1f, respectively, which have the same absolute con-
figuration at the sulfinyl sulfur atom (R) and the opposite configu-
ration on the carbon atom in the amine moieties [(S) and (R),
respectively], led to opposite enantiomers of product 2 with simi-
lar ee’s. The small differences in the ee values of the product may
be explained in terms of ‘matched’ and ‘mismatched’ interactions
with the stereogenic sulfinyl center.
tives7–10 or by other amino derivatives.11–14 Previously, we
,
synthesized a series of chiral tridentate catalysts, containing hy-
droxyl, sulfinyl, and amine moieties, with two stereogenic centers,
one located on the sulfinyl sulfur atom and the other on the carbon
atom in the amine moiety.15 These ligands were found to very effi-
ciently catalyze various enantioselective reactions of asymmetric
carbon–carbon bond formation. Thus, the catalysts with chiral acy-
clic amine moieties turned out to be particularly useful in the ster-
eoselective nitroaldol (Henry) reaction16 and aza-Henry reaction17
while those bearing chiral aziridinyl substituents were useful for
the enantioselective diethylzinc and phenylethynylzinc additions
to aldehydes18,19 and enantioselective conjugate Michael addition
of diethylzinc to enones.20 Moreover, it was possible to obtain each
enantiomer of the products of the above reactions using easily
available enantiopure diastereomeric catalysts. On the basis of all
the aforementioned results, we have decided to study the catalytic
activity of our tridentate catalysts in the enantioselective direct al-
dol reaction.
⇑
Corresponding author.
E-mail address: mrach14@wp.pl (M. Rachwalski).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.008

1326
M. Rachwalski et al. / Tetrahedron: Asymmetry 22 (2011) 1325–1327
NR1-R2
HO
O
S
1
amines
H
H3C
NH2
H3C
NH2
Pri
Me
Me
H
Me
Pri
H
N
H
N
N
H
H
N
H
H
g
c
d
e,f
a
b
a 2,2`-dimethylaziridine
b (-)-(S)-2-isopropylaziridine
c (+)-(R)-2-isopropylaziridine
d (-)-(S)-2-methylaziridine
e (-)-(S)-1-phenylethylamine
f (+)-(R)-1-phenylethylamine
g (-)-(S)-1-(1`-naphthyl)ethylamine
Scheme 1. Ligands for the asymmetric aldol reaction.
O
OH
O
O
OH
O
O
Ligand 1g
+
O
Ligand 1
rt
rt
R
H
R
H
+
3
Scheme 3. Asymmetric aldol condensation of acetone with various aldehydes
promoted by catalyst 1g.
2
Scheme 2. Screening of ligands 1.
for the reaction while the absolute configurations of the resulting
adducts are the same in each case.
Table 1
Screening of catalysts 1
As mentioned above, each diastereomeric catalyst is easily
accessible and leads to the formation of the opposite enantiomer
of the addition product. This means that the desired enantiomer
of the product can be obtained by choosing the appropriate enan-
tiomeric amine to synthesize a diastereomeric catalyst starting
from the same chiral precursor previously described.15
Entry
Catalyst
Product 2
a
Yield (%)
[a
]
D
eeb (%)
Absolute configurationc
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
36
56
54
45
92
89
98
+17.05
+29.24
ꢀ30.45
+22.54
+57.25
ꢀ54.80
+59.08
28
48
50
37
94
90
94
(R)
(R)
(S)
(R)
(R)
(S)
(R)
3. Conclusion
Chiral tridentate catalysts, which contain two stereogenic cen-
ters, one located on the sulfinyl sulfur atom, and the other on the
carbon atom in the amine moiety, were found to be very efficient
catalysts for the enantioselective direct aldol reaction. The stereo-
genic centers located in the amine moieties exerted a decisive
influence on the stereochemistry of the reaction and the absolute
configuration of the products. Each enantiomer of the product
may be obtained by using easily available diastereomeric catalysts.
1g
a
b
c
In chloroform, c 1.
Determined using chiral HPLC.
Taken from the literature.2
2.2. Asymmetric aldol reaction in the presence of catalyst 1g
Having obtained the best results with ligand 1g, we then
decided to determine the scope of its activity. To this end, it was
used to catalyze the title transformation performed with a series
of aldehydes (Scheme 3). The results are shown in Table 2.
The results shown in Tables 1 and 2 clearly indicate that the se-
lected ligand 1g and the two diastereomeric ligands 1e and 1f are
very effective catalysts for the title reaction, with all leading to the
appropriate chiral aldols in high chemical yields and with high
enantiomeric excesses. Both aryl and alkyl aldehydes are suitable
4. Experimental
4.1. General
Unless otherwise specified, all reagents were purchased from
commercial suppliers. Acetone, benzaldehyde, 2-chlorobenzalde-
hyde, and isobutyraldehyde were distilled before use. 4-Nitro-
and 4-bromobenzaldehyde were crystallized before use. NMR

M. Rachwalski et al. / Tetrahedron: Asymmetry 22 (2011) 1325–1327
1327
Table 2
Asymmetric aldol condensation of acetone with various aldehydes in the presence of catalyst 1g
Entry
R
Product 3
a
Symbol
Yield (%)
[
a
]
eeb (%)
Absolute configurationc
D
1
2
3
4
5
6
C6H5
a
b
c
d
e
f
98
89
82
85
96
95
+59.1
+57.2
+52.0
+52.7
+66.8
+7.3
94
85
91
87
92
96
(R)
(R)
(R)
(R)
(R)
(R)
4-BrC6H4
2-ClC6H4
4-NO2C6H4
4-MeOC6H4
i-Pr
a
b
c
In chloroform, c 1.
Determined using chiral HPLC.
Taken from the literature.2,22,23
spectra were recorded on a Bruker instrument at 600 MHz with
CDCl3 as a solvent and relative to TMS as an internal standard. Data
are reported as s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, and b = broad. Optical rotations were measured on
a Perkin–Elmer 241 MC polarimeter with a sodium lamp at room
temperature (c 1). Melting points were measured on a MELTEMP
apparatus and are uncorrected. Column chromatography was car-
ried out using Merck 60 silica gel. TLC was performed on Merck
60 F254 silica gel plates. Visualization was accomplished with UV
light or iodine vapor. The enantiomeric excess (ee) values were
determined by chiral HPLC (Knauer, Chiralcel OD).
4.2.5. (R)-4-Hydroxy-4-(4-methoxyphenyl)butan-2-one 3e
Colorless oil. 1H NMR (CDCl3): d = 2.21 (s, 3H), 2.81 (dd, J = 3.0,
18.0 Hz, 1H), 2.91 (dd, J = 9.0, 18.0 Hz, 1H), 3.21 (br s, 1H), 3.82
(s, 3H), 5.03 (dd, J = 3.0, 9.0 Hz, 1H), 6.89–6.92 (m, 2H), 7.29–7.31
(m, 2H). Other spectroscopic data of compound 3e are in agree-
ment with those reported in the literature.22
4.2.6. (R)-4-Hydroxy-5-methylhexan-2-one 3f
Yellow oil. 1H NMR (CDCl3): d = 0.93 (d, J = 6.0 Hz, 3H), 0.94 (d,
J = 6.0 Hz, 3H), 1.62–1.73 (m, 1H), 2.21 (s, 3H), 2.43–2.65 (m, 2H),
3.80–3.86 (m, 1H). Other spectroscopic data of compound 3f are
in agreement with those reported in the literature.2
Chiral tridentate catalysts were obtained using the previously
described procedure.15,18
Acknowledgments
4.2. General procedure for the asymmetric direct aldol reaction
Financial support provided by the Polish Ministry of Science
and Higher Education, Grant no. N N204 131140 for PK, is grate-
fully acknowledged.
A round-bottomed flask was charged with catalyst 1 (0.2 mmol)
and acetone (25 mL). The mixture was cooled to 0 °C, after which
the corresponding aldehyde (1 mmol) was added and the mixture
was stirred at room temperature for 24 hours. After this time, ace-
tone was evaporated and the crude mixture was purified via col-
umn chromatography (hexane: ethyl acetate in gradient) to
obtain optically active products 3a–f. The yields, specific rotations,
and enantiomeric excess values are shown in Tables 1 and 2.
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