Highly enantioselective Henry reaction catalyzed by chiral tridentate heteroorganic ligands

Article abstract of DOI:10.1016/j.tetasy.2009.06.015

New tridentate enantiomerically pure heteroatom catalysts, containing hydroxyl, sulfinyl and amino groups, proved to be highly efficient in the enantioselective nitroaldol (Henry) reaction to give the desired adducts in very high yields (up to 90%) and wi

Full text of DOI:10.1016/j.tetasy.2009.06.015

Tetrahedron: Asymmetry 20 (2009) 1547–1549
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective Henry reaction catalyzed by chiral tridentate
heteroorganic ligands
b,
b
a,
Michał Rachwalski a,b, Stanisław Lesniak , Ewelina Sznajder , Piotr Kiełbasinski
*
*
´
´
a
´
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112, 90–363 Łódz, Poland
Department of Organic and Applied Chemistry, University of Łódz, Narutowicza 68, 90-136 Łódz, Poland
b
´
´
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2009
Accepted 18 June 2009
New tridentate enantiomerically pure heteroatom catalysts, containing hydroxyl, sulfinyl and amino
groups, proved to be highly efficient in the enantioselective nitroaldol (Henry) reaction to give the desired
adducts in very high yields (up to 90%) and with ees up to 98%. The influence of the stereogenic centres
located on the sulfinyl sulfur atom and in the amine moiety is also discussed.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
their activity in the Henry reaction, hoping that the stereogenic sul-
finyl moiety would in this case exert strong stereoinduction.12
The nitroaldol (Henry) reaction, particularly its stereoselective
version, has recently attracted great attention, as can be seen from
the number of recent publications.1 This is obviously due to the fact
that the reaction products, enantiomerically pure (or at least en-
riched) 2-nitroalcohols, can be easily transformed into valuable chi-
ral building blocks via the appropriate transformations of both the
hydroxy and nitro groups. The asymmetric Henry reaction rests
upon the aldol-type addition of a nitroalkane to an aldehyde, per-
formed in the presence of metal complexes with chiral ligands.
Among the ligands, a variety of chiral amine derivatives have been
used, including diamides2 and those based on chiral diamines,
trans-1,2-diaminocyclohexane,3 bis-oxazolines,4 oxazolidines5 and
aziridines.6 Although the use of copper diacetate as the metal com-
ponent seems to be most common, other metal salts have also been
applied.7 Recently, sterically modified salen-chromium complexes
have been successfully used as catalysts to give the 2-nitroalcohols
with ees of up to 94%.8
Over the course of our studies on the application of enzymes in
the synthesis of chiral non-racemic heteroorganic compounds,9 we
have recently reported the synthesis of new enantiomerically pure
tridentate ligands 3 which possess three different nucleophilic
centres capable of binding organometallic reagents: the hydroxyl,
sulfinyl and amino moieties. They were prepared via an enzyme-
catalyzed desymmetrization of prochiral dihydroxy sulfoxide 1
followed by the relevant chemical transformations comprising the
introduction of enantiomeric C-chiral amines (Scheme 1).10
Although some of them proved to be weak catalysts for the stereose-
lective addition of diethylzinc to aldehydes,11 we decided to study
2. Results and discussion
2.1. Screening of the ligands
To check the ability of the ligands to catalyze the enantioselective
nitroaldol reaction, we chose the addition of nitromethane to benz-
aldehyde as a reference transformation. The reactions were per-
formed under standard conditions, using copper acetate as the
metal component (Scheme 2). The results are collected in Table 1.
Inspection of Table 1 shows that both the yields and ees of the
product depend strongly on the structure of the ligand. Ligand 3a,
which was a relatively good catalyst,10 and ligands 3d–f which were
very efficient catalysts11 in the diethylzinc addition to benzaldehyde
turned out to be disappointingly weak in the Henry reaction.13 On
the other hand, ligands 3b and 3c, which were inefficient in the
diethylzinc addition to benzaldehyde,10 proved to be almost per-
fectly enantioselective in the Henry reaction. In contrast to their cat-
alytic activity in the diethylzinc addition, in which the sulfinyl
stereogenic centre exerted a strong influence on the stereochemis-
try of the reaction, the decisive role in the Henry reaction was played
by the stereogenic centres located in the amine moieties. This is vis-
ible in entries 2 and 3, and 5 and 6 where the use of diastereomeric
ligands 3b and 3c, and 3e and 3f, respectively, having the same abso-
lute configuration at the sulfinyl sulfur atom (R) and opposite on the
carbon atom in the amine moieties [(S) and (R), respectively], led to
opposite enantiomers of adduct 4a with almost the same ees.
2.2. Henry reaction with various aldehydes in the presence of
catalyst 3c
* Corresponding authors. Tel.: +48 42 6815832; fax: +48 42 6803260.
E-mail addresses: slesniak@chemul.uni.lodz.pl (S. Les´niak), piokiel@bilbo.cbmm.
lodz.pl (P. Kiełbasin´ ski).
Having obtained promising results with ligands 3b and 3c, we
then decided to check the scope of the reaction. The title reaction
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.06.015

1548
M. Rachwalski et al. / Tetrahedron: Asymmetry 20 (2009) 1547–1549
HO
OH
HO
NR1
R2
AcO
OH
O
S
O
O
S
S
, lipase
CHCl3
AcO
3
(+)-(R)-2
Amines
1
H
Pri
H
H3C
Me
Me
NH2
H
Pr1
H
H3C
N
N
H
N
H
CH3
H
NH2
f
e
d
a
b,c
a) (−)-cis-myrtanylamine
b) (−)-(S)-1-(1'-naphthyl)ethylamine
c) (+)-(R)-1-(1'-naphthyl)ethylamine
d) 2,2-dimethylaziridine
e) (−)-(S)-2-isopropylaziridine
f) (+)-(R)-2-isopropylaziridine
Scheme 1. Synthesis of tridentate ligands.
H
O
CH2NO2
OH
ligand, Cu(OAc)2
MeNO2
Ph
C
Ph
+
EtOH, rt
H
Scheme 2. Screening of ligands 3.
Table 1
Screening of ligands 3
alkyl aldehydes are suitable for the reaction while the absolute
configurations of the resulting adducts are the same in each case.
Since both diastereomers of this ligand, that is, 3b and 3c, are avail-
able, and each of them leads to the formation of the opposite enan-
tiomer of the product (Table 1, entries 2 and 3), this approach
constitutes an easy access to the desired sterically defined 2-
nitroalcohols.
Entry
Ligand
Adduct 4a
a
Yield (%)
[
a
]
D
ee (%)b
Absolute configuration
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
30
90
87
40
81
85
À10
+22
À22
À5
48
98
98
24
15
20
(R)
(S)
(R)
(R)
(R)
(S)
À3.5
+4.1
3. Conclusions
a
In chloroform (c 1).
Determined using chiral HPLC.
b
The chiral tridentate ligands, which contain two stereogenic
centres, one located on the sulfinyl sulfur atom, and the other on
the carbon atom in the amine moiety, were found to be very effi-
cient catalysts for the enantioselective nitroaldol (Henry) reaction
performed with aryl and alkyl aldehydes in the presence of copper
acetate. The stereogenic centres located in the amine moieties ex-
erted a decisive influence on the stereochemistry of the reaction
and the absolute configuration of the products. Each enantiomer
was performed using a series of aldehydes in the presence of ligand
3c as a catalyst (Scheme 3). The results are collected in Table 2.
The results clearly indicate that the selected ligand 3c effi-
ciently catalyzes the title reaction to give the appropriate products
in high yields and with high enantiomeric excesses. Both aryl and
H
O
CH2NO2
catalyst 3c, Cu(OAc)2
EtOH, rt
R
C
R
MeNO2
+
OH
H
4
Scheme 3. Nitroaldol reaction with various aldehydes.

M. Rachwalski et al. / Tetrahedron: Asymmetry 20 (2009) 1547–1549
1549
Table 2
4.3.3. (R)-1-(2-Nitrophenyl)-2-nitroethanol 4c
Nitroaldol reaction with various aldehydes
Dark solid, yield = 87%. Enantiomeric excess was determined by
HPLC with a Chiralpak AS column (90:10 hexane/isopropanol,
0.8 mL/min, 215 nm); major enantiomer tR = 17.6 min, minor
Entry
R
Adduct 4
Symbol
Yield (%)
[
a
]
D
eeb (%)
Absolute
configuration
a
enantiomer tR = 19.2 min; ee = 90%; [a]D = +228.0 (c 1.00, CHCl3).
All spectroscopic data of compound 4c are in good agreement with
1
2
3
4
5
6
Ph
a
b
c
d
e
f
87
90
87
86
78
85
À22.0
À45.5
98
95
90
87
85
90
(R)
(R)
(R)
(R)
(R)
(R)
those reported in the literature.4
2-MeOC6H4
2-NO2C6H4
2-ClC6H4
Ph(CH2)2
n-Bu
+228.0
À50.4
+14.2
À9.0
4.3.4. (R)-1-(2-Chlorophenyl)-2-nitroethanol 4d
Colourless oil yield = 86%. Enantiomeric excess was determined
by HPLC with a Chiralpak AS column (97:3 hexane/isopropanol,
0.8 mL/min, 215 nm); major enantiomer tR = 53.0 min, minor
a
In chloroform (c 1).
Determined using chiral HPLC.
b
enantiomer tR = 57.2 min; ee = 87%; [
a
]
D = À50.4 (c 1.00, CHCl3).
All spectroscopic data of compound 4d are in good agreement
with those reported in the literature.4
of the product may be obtained by using easily available diastereo-
meric ligands.
4.3.5. (R)-1-Nitro-4-phenylbutan-2-ol 4e
White solid yield = 78%. Enantiomeric excess was determined
by HPLC with a Chiralpak AS column (87:13 hexane/isopropanol,
0.8 mL/min, 215 nm); major enantiomer tR = 21.4 min, minor
4. Experimental
4.1. General
enantiomer tR = 20.1 min; ee = 85%; [a]D = +14.2 (c 1.00, CHCl3).
All spectroscopic data of compound 4e are in good agreement with
those reported in the literature.4
The enzymes were purchased from AMANO or FLUKA. The NMR
spectra were recorded on a Bruker instrument at 200 MHz with
CDCl3 and CD3OD as solvents. Optical rotations were measured
on a Perkin–Elmer 241 MC polarimeter (c 1). Column chromatogra-
phy was carried out using Merck 60 silica gel. TLC was performed
on Merck 60 F254 silica gel plates. The enantiomeric excess (ee) val-
ues were determined by chiral HPLC (Varian Pro Star 210, Chir-
alpak AS).
4.3.6. (R)-1-Nitrohexan-2-ol 4f
Colourless oil yield = 85%. Enantiomeric excess was determined
by HPLC with a Chiralpak AS column (98:2 hexane/isopropanol,
0.8 mL/min, 215 nm); major enantiomer tR = 34.2 min, minor
enantiomer tR = 46.1 min; ee = 90%; [
a
]
D = À9.0 (c 1.00, CHCl3). All
spectroscopic data of compound 4f are in good agreement with
those reported in the literature.4
4.2. Synthesis of tridentate ligands 3a–f
Acknowledgement
All enantiomerically pure ligands 3a–f were prepared using a
methodology described previously.10,11
Financial support provided by the Polish Ministry of Science
and Higher Education, Grant No. PBZ-KBN-126/T09/03, is gratefully
acknowledged.
4.3. Copper acetate—catalyzed Henry reaction of nitromethane
with aldehydes—general procedure
References
Ligand 3 (0.055 mmol) and Cu(OAc)2 monohydrate (10 mg,
0.05 mmol) were placed in
a round-bottomed flask. Ethanol
1. For recent reviews see: (a) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem.
2007, 2561–2574; (b) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C.
Tetrahedron: Asymmetry 2006, 17, 3315–3326; (c) Palomo, C.; Oiarbide, M.;
Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442–5444.
(1.5 mL) was added and the mixture was stirred for 1 h. After that,
nitromethane (0.54 mL, 10 mmol) and the corresponding aldehyde
(1 mmol) were added. After stirring for 48 h the volatile compo-
nents were evaporated and the crude product was purified by col-
umn chromatography (chloroform).
2. Nitabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett. 2008, 49, 272–276.
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3. Kowalczyk, R.; Sidorowicz, Ł.; Skarzewski, J. Tetrahedron: Asymmetry 2008, 19,
2310–2315, and references therein.
4. Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2003, 125, 12692–12693.
4.3.1. (R)-1-Phenyl-2-nitroethanol 4a
5. Liu, S.; Wolf, C. Org. Lett. 2008, 10, 1831–1834.
Colourless oil yield = 87%. Enantiomeric excess was determined
by HPLC with a Chiralpak AS column (85:15 hexane/isopropanol,
0.8 mL/min, 215 nm); major enantiomer tR = 12.1 min, minor
6. Bulut, A.; Aslan, A.; Dogan, O. J. Org. Chem. 2008, 73, 7373–7375.
7. Arai, T.; Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. J. Org. Chem.
2008, 73, 4903–4906, and references therein.
_
8. Kowalczyk, R.; Kwiatkowski, P.; Skarzewski, J.; Jurczak, J. J. Org. Chem. 2009, 74,
enantiomer tR = 14.2 min; ee = 98%; [
a
]
D = À22.0 (c 1.00, CHCl3).
753–756.
´
9. Kiełbasinski, P.; Mikołajczyk, M. In Future Directions in Biocatalysis; Matsuda, T.,
All spectroscopic data of compound 4a are in good agreement with
Ed.; Elsevier, 2007; pp 159–203.
those reported the in literature.4
10. Rachwalski,M.;Kwiatkowska,M.;Drabowicz,J.;Kłos,M.;Wieczorek,W.M.;Szyrej,
M.; Sieron´, L.; Kiełbasin´ ski, P. Tetrahedron: Asymmetry 2008, 19, 2096–2101.
11. In contrast to ligands 3a–c,10 ligands 3d–f turned out to be efficient catalysts
for the diethylzinc addition to benzaldehyde; for their synthesis and
application see Les´niak, S.; Rachwalski, M.; Sznajder, E.; Kiełbasin´ ski, P.,
submitted for publication.
12. Mikołajczyk, M.; Drabowicz, J.; Kiełbasin´ ski, P. Chiral Sulfur Reagents: Application
in Asymmetric and Stereoselective Synthesis; CRC Press: Boca Raton, 1997.
13. Ferrocenyl(hydroxymethyl)aziridines were recently found to be good catalysts
for the Henry reaction. However, instead of copper acetate, diethylzinc was
used as the metal component: see Ref. 6.
4.3.2. (R)-1-(2-Methoxyphenyl)-2-nitroethanol 4b
Yellow oil, yield = 90%.Enantiomeric excess was determined by
HPLC with a Chiralpak AS column (90:10 hexane/isopropanol,
0.8 mL/min, 215 nm); major enantiomer tR = 14.6 min, minor
enantiomer tR = 17 min; ee = 95% [
a
]
D = À45.5 (c 1.00, CHCl3). All
spectroscopic data of compound 4b are in good agreement with
those reported in the literature.4