Enantioselective Henry reaction catalyzed by copper(II) - Cinchona alkaloid complexes

Article abstract of DOI:10.1016/j.tetasy.2011.02.003

An enantioselective Henry reaction was efficiently carried out under mild reaction conditions in the presence of catalytic 9-epi and natural Cinchona alkaloids and copper (II) acetate. The best catalytic performance was observed for native quinine (12 mol

Full text of DOI:10.1016/j.tetasy.2011.02.003

Tetrahedron: Asymmetry 22 (2011) 351–355
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective Henry reaction catalyzed by copper(II)—Cinchona
alkaloid complexes
⇑
_
´
Mariola Zielinska-Błajet, Jacek Skarzewski
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective Henry reaction was efficiently carried out under mild reaction conditions in the pres-
ence of catalytic 9-epi and natural Cinchona alkaloids and copper (II) acetate. The best catalytic perfor-
mance was observed for native quinine (12 mol %) and Cu(OAc)2 (10 mol %). Aromatic and aliphatic
Received 5 January 2011
Accepted 3 February 2011
Available online 1 March 2011
aldehydes with nitromethane and its a-substituted derivatives provided the corresponding b-nitroalco-
hols in good to reasonable yields, high syn-diastereoselectivity, and (S)-enantioselectivity of up to 94% ee.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
selectivities.5a,b However, in 2005, Jørgensen et al. reported an ele-
gant highly stereoselective aza-Henry reaction using Cinchona
Asymmetric Henry (nitroaldol) and aza-Henry reactions offer a
simple route to chiral b-nitroalcohols and b-nitroamines, impor-
tant synthetic intermediates, which are easily transformed into
various difunctionalized derivatives and precursors of biologically
active compounds.1 For this reason much effort has been devoted
to the development of metal-catalyzed and organocatalytic ver-
sions of this reaction.2,3 The effective catalytic process requires
both a Brønsted base (to deprotonate the nitro-compound) and a
Lewis acid (to activate the carbonyl group). With respect to this,
copper complexes of chiral amines2g,4 were successfully applied
as catalysts, giving the corresponding b-nitroalcohols with high
ee. Derivatives of Cinchona alkaloids (cinchonine, cinchonidine,
quinine, and quinidine, Fig. 1) have already been tested in both
Henry and aza-Henry reactions.5 The direct organocatalytic appli-
cation of natural Cinchona alkaloids in asymmetric nitroaldol reac-
tions requires high pressure conditions and only gave moderate
alkaloids as a chiral Brønsted base in combination with a copper(II)
chiral bisoxazoline complex as a chiral Lewis acid. The diastereose-
lectivity was controlled by quinine, while the configuration of the
main product was determined by the Lewis acid ligand.5c When C-
9-epi-thioles derived from Cinchona alkaloids were tested as chiral
ligands in the Cu-catalyzed asymmetric Henry reaction, the pro-
cess went smoothly with an enantioselectivity of up to 83%.2k All
these results encouraged us to study the use of natural Cinchona
alkaloids in the direct Henry reaction carried out in the presence
of copper(II) acetate.
2. Results and discussion
We examined the catalytic performance of the alkaloids in a
model nitroaldol reaction between benzaldehyde and nitrometh-
ane. The reaction was carried out in the presence of 12 mol % of
alkaloid and 10 mol % of hydrated copper acetate (Scheme 1).
OH
Alkaloid, Cu(OAc)2xH2O
R
R
N
NO2
PhCHO + CH3NO2
Ph
*
i-PrOH, 0°C
Scheme 1.
(8S)
(9R)
N
N
(8R)
(9S)
OH
HO
N
The results of the preliminary screening are summarized in
Table 1. Thus, all the alkaloids of the 9-native configuration
catalyzed the enantioselective reaction giving nitroaldol in good
yield. The alkaloid with an (8R)-configuration, gave mainly the
(R)-product while those with an (8S)-configuration produced
mostly the (S)-isomer. We also tested other solvents (dichloro-
methane, acetonitrile, ethanol, etc.) and i-PrOH was chosen as
the most suitable one. The standard reaction performed with
R = OMe, quinine
R = OMe, quinidine
R = H, cinchonine
R = H, cinchonidine
Figure 1.
⇑
Corresponding author.
E-mail address: jacek.skarzewski@pwr.wroc.pl (J. Skarzewski).
_
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.003

_
´
352
M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 22 (2011) 351–355
Table 2
quinine at À20 °C gave less yield (53%) and 81% ee. When quinine
was used in the absence of copper acetate (entry 8), a very small
excess of the (R)-product was obtained. Furthermore, the 9-epi
alkaloids (entries 6 and 7) led to nearly negligible enantioselectiv-
ities. An almost racemic product was obtained using quinine with
Zn(OAc)2, Co(OAc)2 or VO(OAc)2, but when a system of quinine
(12 mol %) and Et2Zn (10 mol %) was applied in toluene at À20 °C
for 3 days, a 94% yield of the nitroaldol with 19% ee (R) resulted.
Furthermore, the results in Table 1 show that 6’-methoxy alkaloids
(quinidine and quinine, entries 3 and 4) performed better than the
unsubstituted ones (cinchonidine and cinchonine, entries 1 and 2).
We have already observed the same tendency with the 9-epi-thi-
oles of quinine and other alkaloids, where it could be ascribed to
the formation of an additional hydrogen bond, thus stabilizing
the corresponding transition state of the similar copper-catalyzed
Henry reaction.2k The same interaction may operate here; how-
ever, an important difference between these catalysts should be
noted. Thus, the 9-epi-HS-alkaloids gave much higher ee’s than
their epimers (e.g., 9-epi-HS-quinine gave 83% ee, while 9-HS-qui-
nine gave 14% ee only)2k and quite the opposite tendency is ob-
Nitroaldol reaction of benzaldehyde and nitromethane catalyzed by quinine/
Cu(OAc)2
a
Entry
Ligand added
Amount
(mol %)
Yield (%)
ee b(%)
configurationc
1
2
3
4
5
6
7
(8S,9R)-Quinine
(8S,9R)-Quinine
(8S,9R)-Quinine
(8S,9R)-Quinine
(8S,9R)-Quinine
(8S,9R)-Quinine
(8S,9R)-Quinine
(8S,9S)-epi-Quinine
(8S,9R)-Quinine
(8R,9S)-Quinidine
5
8
51
56
78
87
89
91
76 (S)
77 (S)
79 (S)
86 (S)
66 (S)
57 (S)
10
12
16
24
8.4
3.6
8.4
3.6
73
68
56 (S)
49 (S)
8
a
The reactions were carried out on a 0.5 mmol scale, in the presence of quinine,
Cu(OAc)2ÁH2O (10 mol %) in i-PrOH (2 mL) at 0 °C for 3 days.
b
Enantiomeric excess determined by HPLC analysis.
Determined by comparison of the sign of specific rotation and retention time
c
(chiral HPLC) with the literature values.
tained an ee value (entry 8) close to the expected value for two
independent and parallel processes catalyzed by each complex
[calculated 43%, (S)]. A mixture of quinine and epi-quinine (entry
7) gave a result close to the corresponding estimated one [61%
(S)]. Thus, it seems that all the Cinchona alkaloid–Cu(OAc)2 1:1
complexes accommodate both reactants (aldehyde and nitronate
anion), thus facilitating the reaction, although the enantioselectiv-
ity depends on the stereochemical match within the particular dia-
stereomeric arrangement.
served here (Table 1, entries
4 vs 6 and 3 vs 7). The
stereochemical sense of induction for both types of catalysts was
the same, that is, the configuration of the product is tied to the con-
figuration at the C-8 center of the alkaloid.
Table 1
Nitroaldol reaction of nitromethane and benzaldehyde catalyzed by alkaloid/
a
Cu(OAc)2
With the simple catalytic system in hand, we carried out a
Henry reaction between nitromethane and several different alde-
hydes; in all but two cases we obtained the respective nitroalco-
hols in reasonable to good ee and yield (Table 3). For trans-
cinnamaldehyde, the yield was less due to side-reactions while
for o-nitrobenzaldehyde the enantioselectivity observed was poor.
Entry Ligand
Yield
(%)
ee
Absolute
b(%)
configurationc
1
2
3
4
5
6
7
8
(8S,9R)-Cinchonidine
42
55
73
87
84
61
38
100
53
47
59
86
58
2
(S)
(R)
(R)
(S)
(S)
(S)
(R)
(R)
(8R,9S)-Cinchonine
(8R,9S)-Quinidine
(8S,9R)-Quinine
(8S, 9R)-DHQN
(8S,9S)-epi-Quinine
(8R,9R)-epi-Quinidine
(8S,9R)-Quinine without
Cu(OAc)2ÁH2O
Table 3
7
3.5
a
Nitroaldol reaction of aldehydes and nitromethane catalyzed by quinine/Cu(OAc)2
Entry
RCHO
Yield (%)
ee b(%) configurationc
a
1
2
3
4
5
6
7
8
9
Ph
87
86
88
50
17
63
62
57
52
86 (S)
15 (S)
67 (S)
68 (S)
61 (S)
72 (S)
71 (S)
83 (S)
75 (S)
The reactions were carried out on a 0.5 mmol scale, 12 mol % of the respective
o-NO2C6H4
o-MeOC6H4
9-Anthryl
PhCH@CH
c-C6H11
n-C5H11
iso-C4H9
tert-C4H9
alkaloid, 10 mol % of Cu(OAc)2ÁH2O, 10 equiv of CH3NO2 in i-PrOH (2 mL) at 0 °C for
3 days.
b
Enantiomeric excess determined by HPLC analysis.
Determined by comparison of the specific rotation sign and retention time
c
(chiral HPLC) with the literature values.
Since the quinine/copper acetate system was catalytically effec-
tive, we decided to examine it more closely. When copper acetate
dissolved in isopropyl alcohol was treated with an equimolar
amount of quinine, a green complex precipitated slowly. The sub-
sequent addition of nitromethane made a homogeneous solution,
thus forming the other complexed species.
a
The reactions were carried out on a 0.5 mmol scale, in the presence of quinine
(12 mol %), Cu(OAc)2ÁH2O (10 mol %) in i-PrOH (2 mL) at 0 °C for 3 days.
b
Enantiomeric excess determined by HPLC analysis.
c
Determined by comparison of the specific rotation sign and retention time
(chiral HPLC) with the literature values.
Little information on the coordination chemistry of copper(II)
cations–quinine system has appeared in the literature.6 Recently,
three different coordination modes have been suggested and two
of them correspond to a 1:1 copper to ligand ratio. However, more
detailed structures remain obscure and our attempts to obtain a
crystal suitable for the X-ray study were unsuccessful.
In order to gain additional information on the catalytic system,
we carried out the model reaction with different amounts of qui-
nine and quinine used with its pseudoenantiomer (quinidine)
and diastereomer (epi-quinine) (Table 2).
The results shown in Table 2 suggest that the enantioselective
reaction is catalyzed by a quinine–Cu(OAc)2 1:1 complex. An ex-
cess of the ligand lowers the ee, while the total yield increases. This
is in agreement with the outcome observed in the presence of only
quinine (Table 1, entry 8). When using Cu(OAc)2 with a mixture of
70% quinine and 30% quinidine (its pseudoenantiomer) we ob-
These results prompted us to extend this reaction to other
nitroalkanes and to examine the diastereoselectivity (Scheme 2,
Table 4).
The reaction of nitroethane with benzaldehyde was carried out
as before in the presence of quinine/Cu(OAc)2 at 0 °C to mainly give
the syn-product in 78% ee. Lowering temperature to À20 °C led to
an improvement in both diastereo- and enantioselectivities with
no decrease in the yield (Table 4, entry 2). The addition of nitroe-
thane to cyclohexanecarboxaldehyde at À20 °C gave the syn-nitro-
aldol in 60% yield with 82% de and 94% ee (entry 4). However,
when 1-nitropropane was used in this reaction, lowering the tem-
perature resulted in a large decrease in the yield with a less pro-
nounced improvement of selectivity (entries 5 and 6). Finally, the
reaction of 9-anthraldehyde with 1-nitropropane (entry 7) affor-
ded both the syn- (main) and anti-product in 82% and 70% ee,

_
´
353
M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 22 (2011) 351–355
quinine (12 mol%)
OH
OH
O
Cu(OAc)2xH2O (10 mol%)
R2
+
R2
+
R1
R2CH2NO2
R1
i-PrOH
R1
H
NO2
anti
NO2
syn
Scheme 2.
Table 4
Henry reaction of aldehydes and nitroalkanes catalyzed by quinine/Cu(OAc)2
a
Entry
R1
R2
T (°C)
Yieldb (%)
drc [syn/anti]
eed,e [syn] (%)
eed,e [anti] (%)
1
2
3
4
5
6
7
Ph
Ph
CH3
CH3
CH3
CH3
CH3CH2
CH3CH2
CH3CH2
0
À20
0
99
98
99
60
62
39
87
65:35
76:24
83:17
91:9
81:19
86:14
81:19
78 (1S,2S)
94 (1S,2S)
88 (1S,2S)
94 (1S,2S)
81 (1S,2S)
88 (1S,2S)
82 (1S,2S)
46 (1S,2R)
71 (1S,2R)
62 (1S,2R)
63 (1S,2R)
60 (1S,2R)
66 (1S,2R)
70 (1S,2R)
c-C6H11
c-C6H11
c-C6H11
c-C6H11
9-Anthryl
À20
0
À20
0
a
b
c
The reactions were carried out on a 0.5 mmol scale, 12 mol % of quinine, 10 mol % of Cu(OAc)2ÁH2O, 10 equiv of nitroalkane in i-PrOH (2 mL) for 3 days.
Combined yields of syn and anti isomers.
Determined by 1H NMR spectroscopy of the crude product.
d
e
Determined by chiral HPLC.
The absolute configurations were established by comparison with literature data.
respectively. When the reaction was carried out at À20 °C, it was
completely halted. The last diastereomeric products were sepa-
rated by chromatography to give pure syn- and anti-isomers in
90% and 97% ee, correspondingly.
4.2. General procedure for the nitroaldol reaction
The ligand (0.06 mmol, 12 mol %) and Cu(OAc)2ÁH2O (10.0 mg,
0.05 mmol, 10 mol %) were dissolved in i-PrOH (1 mL) and the mix-
ture was stirred for 3 h at rt to give a blue-green solution. The reac-
tion mixture was cooled to 0 °C (or À20 °C). The respective
aldehyde (0.5 mmol, 1 equiv) and nitroalkane (5.0 mmol, 10 equiv)
were added with an additional 1 mL of i-PrOH. After 3 days, the
crude product was isolated by column chromatography (hexane/
AcOEt 6:1) to give b-nitroalcohol or desired b-nitroalcohols as a
mixture of diastereomers.
3. Conclusion
In conclusion, we have found that a simple catalytic system
made of quinine and copper acetate increases the diastereoselec-
tivity and enantioselectivity of Henry reactions of aromatic and ali-
phatic aldehydes with nitromethane and its
derivatives.
a-substituted
4.2.1. 2-Nitro-1-phenylethan-1-ol
The enantiomeric excess was determined by HPLC (Chiracel
OD-H), hexane/i-PrOH 90:10, 1.0 mL/min, k = 225 nm, enantiomer
(R) Rt = 13.9 min, enantiomer (S) Rt = 17.3 min. The absolute
configuration was assigned by comparison of the retention times
in HPLC and specific rotation signs with the literature data.2d,g,i,k,8,9
The spectroscopic data were in accord with the literature
values.2d,i–k,8
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were measured on a Bruker CPX
(1H, 300 MHz) spectrometer using TMS as the internal standard.
The reported coupling constants were directly observed on the
spectra. IR spectra were recorded on a Perkin–Elmer 1600 FTIR
spectrophotometer. Optical rotations at 578 nm were measured
using an Optical Activity Ltd Model AA-5 automatic polarimeter.
The enantiomeric composition of the nitroaldols was determined
by HPLC analysis using a chiral stationary phase (Chiracel OD-H
or Daicel Chiralpak AD-H). The absolute configuration was as-
signed by comparison of the retention time and the sign of the spe-
cific rotation with the literature data. The absolute stereochemistry
of both diastereomers was assigned by comparison of the retention
times in HPLC to the literature data. Diastereomeric ratios of the
syn/anti products were determined using 1H NMR spectroscopy.
High-resolution mass spectra (HRMS) were recorded on a Waters
LCD Premier XE HRMS apparatus using ESI technique. Separations
of products by chromatography were performed on Silica Gel 60
(230–400 mesh) purchased from Merck. Cinchona alkaloids were
commercially available, epi-quinine and epi-quinidine were pre-
pared according to a general procedure described in Ref. 7. Liquid
aldehydes were freshly distilled before use.
4.2.2. 1-(2-Nitrophenyl)-2-nitroethan-1-ol
The enantiomeric excess was determined by HPLC (Chiralpak
OD-H), hexane/i-PrOH 90:10, 1.0 mL/min, k = 210 nm, minor enan-
tiomer (R) Rt = 14.9 min, major enantiomer (S) Rt = 16.8 min. The
absolute configuration was assigned by comparison of the reten-
tion times in HPLC and specific rotation signs with the literature
data.2i,8 The spectroscopic data were in accord with the literature
values.2i,j,8
4.2.3. 1-(2-Methoxyphenyl)-2-nitroethan-1-ol
The enantiomeric excess was determined by HPLC (Chiralpak
OD-H), hexane/i-PrOH 90:10, 1.0 mL/min, k = 210 nm, minor enan-
tiomer (R) Rt = 12.4 min, major enantiomer (S) Rt = 14.9 min. The
absolute configuration was assigned by comparison of the reten-
tion times in HPLC and specific rotation signs with the literature
data.2i,9 The spectroscopic data were in accord with the literature
values.2i,j,8

_
´
M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 22 (2011) 351–355
354
4.2.4. 1-(Anthracene-9-yl)-2-nitroethan-1-ol
The enantiomeric excess was determined by HPLC (Chiralpak
OD-H), hexane/i-PrOH 90:10, 1.0 mL/min, k = 210 nm, minor enan-
Diastereomeric ratios (syn/anti) were determined by 1H NMR.
The absolute configuration of both diastereomers was assigned
by comparison of the retention times in HPLC with the literature
data.2d–f,j,l 1H NMR spectroscopic data were in agreement with
the literature values.2i,k
tiomer (R) Rt = 16.8 min, major enantiomer (S) Rt = 26.5 min; [a] =
D
À10.5 (c 0.16, CH2Cl2, 68% ee). The absolute configuration was as-
signed by analogy to other compounds in this work. 1H NMR
(300 MHz, CDCl3) d 3.03 (d, J = 3.2 Hz, 1H, OH), 4.54 (dd, J = 13.5,
2.8 Hz, 1H, CHNO2), 5.35 (dd, J = 13.5, 10.6 Hz, 1H, CHNO2), 6.98
(dd, J = 10.6, 2.8 Hz, 1H, CHOH), 7.46–7.53 (m, 4H, ArH), 7.95–
8.00 (m, 2H, ArH), 8.46 (s, 1H, ArH), 8.56 (d, J = 8.4 Hz, 2H, ArH).
13C NMR (75 MHz, CDCl3) d 68.3, 79.6, 123.6, 124.5, 125.2, 125.5,
126.8, 126.9, 127.5, 129.3, 129.6, 130.5, 131.6, 133.5, 134.1,
135.7. IR (film): 3454, 3064, 2926, 1557, 1379, 1316, 1094, 734,
694 cmÀ1. HRMS (ESI(À), [MÀH+]À) calcd for [C16H13NO3ÀH+]À
266.0817; found 266.0835.
4.2.11. 1-Cyclohexyl-2-nitropropan-1-ol
Chiralpak AD-H, n-hexane/i-PrOH 95:5, 0.8 mL/min, k = 225 nm,
antiminor (1R,2S) Rt = 14.0, antimajor (1S,2R) Rt = 15.9, synmajor (1S,2S)
Rt = 15.1, synminor (1R,2R) Rt = 20.9 min.
Diastereomeric ratios (syn/anti) were determined by 1H NMR
spectroscopy. The absolute configuration of both diastereomers
was assigned by comparison of the retention times in HPLC with
the literature data.4b,10a,d,e The chemical shifts of protons adjacent
with carbons C-1, C-2 as well as methyl groups were in agreement
with those reported in the literature.4b,10a,d,e
4.2.5. (S,E)-1-Nitro-4-phenylbut-3-en-2-ol
4.2.12. 1-Cyclohexyl-2-nitrobutan-1-ol
The enantiomeric excess was determined by HPLC (Chiralpak
AD-H), hexane/i-PrOH 95:5, 1.0 mL/min, k = 210 nm, minor enan-
tiomer (R) Rt = 35.1 min, major enantiomer (S) Rt = 36.5 min. The
absolute configuration was assigned by comparison of the reten-
tion times in HPLC and specific rotation signs with the literature
data.2i,l,9 The spectroscopic data were in agreement with the liter-
ature values.2d,i,j,l,9
Chiralpak AD-H, n-hexane/i-PrOH 97:3, 0.5 mL/min, k = 210 nm,
antiminor (1R, 2S) Rt = 25.9, antimajor (1S,2R) Rt = 26.5, synmajor (1S,2S)
Rt = 28.9, synminor (1R,2R) Rt = 46.2 min.
Diastereomeric ratios (syn/anti) were determined by 1H NMR.
Absolute configuration of both diastereomers was assigned by
comparison of the retention times in HPLC with the literature da-
ta.4b,10b,e The chemical shifts of protons adjacent to carbons C-1,
C-2 as well as methyl groups were in agreement with those re-
ported in the literature.4b,10b,e
4.2.6. 1-Cyclohexyl-2-nitroethan-1-ol
The enantiomeric excess was determined by HPLC (Chiralpak
AD-H), hexane/i-PrOH 97:3, 0.8 mL/min, k = 225 nm, minor enan-
tiomer (R) Rt = 27.7 min, major enantiomer (S) Rt = 29.5 min. The
absolute configuration was assigned by comparison of the reten-
tion times in HPLC and specific rotation signs with the literature
data.2k,8,9 The spectroscopic data were in agreement with the liter-
ature values.2d,k,l,8
4.2.13. 1-(Anthracene-9-yl)-2-nitrobutan-1-ol
Chiracel OD-H, n-hexane/i-PrOH 97:3, 0.8 mL/min, k = 225 nm,
antiminor (1R,2S) Rt = 16.3, antimajor (1S,2R) Rt = 12.3, synmajor
(1S,2S) Rt = 28.2, synminor (1R,2R) Rt = 30.8 min. The absolute config-
urations of both diastereomers were determined by analogy to
published HPLC retention times of similar compounds.4b,10c The
mixture of diastereomers was separated using chromatography
giving diastereomerically pure nitroaldols:
4.2.7. 1-Nitroheptan-2-ol
The enantiomeric excess was determined by HPLC (Chiralpak
AD-H), hexane/i-PrOH 98:2, 1.0 mL/min, k = 210 nm, minor enan-
tiomer (R) Rt = 30.9 min, major enantiomer (S) Rt = 41.6 min. The
absolute configuration was assigned by comparison of the reten-
tion times in HPLC and specific rotation signs with the literature
data.2a,l The spectroscopic data were in agreement with the litera-
ture values.2a,l
4.2.13.1.
syn-(1S,2S)-1-(Anthracene-9-yl)-2-nitrobutan-1-ol.
0.71
Solidified brown oil; 1H NMR (300 MHz, CDCl3)
d
(t, J = 7.3 Hz, 3H, CH3), 1.52–1.63 (m, 1H, CHCHHCH3), 1.80–1.84
(m, 1H, CHCHHCH3), 2.76 (br s, 1H, OH), 5.47 (dt, J = 10.2, 3.1 Hz,
1H, CHNO2), 6.66 (dd, J = 10.1, 3.1 Hz, 1H, CHOH), 7.47–7.56 (m,
4H, ArH), 7.97 (t, J = 8.1 Hz, 2H, ArH), 8.38–8.49 (m, 2H, ArH),
8.50 (s, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 10.3, 24.4, 71.4,
94.7, 123.6, 125.0, 125.7, 127.2, 128.0, 129.2, 129.3, 129.6, 129.9,
130.1, 131.1, 132.2, 133.5, 134.1. IR (film): 3479, 3054, 2973,
2936, 1557, 1373, 1284, 735, 694 cmÀ1. HRMS (ESI(À), [MÀH+]À)
calcd for [C18H17NO3ÀH+]À 294.1130; found 294.1105.
4.2.8. 4-Methyl-1-Nitropentan-2-ol
The enantiomeric excess was determined by HPLC (Chiralpak
AD-H), hexane/i-PrOH 95:5, 1.0 mL/min, k = 210 nm, minor enan-
tiomer (R) Rt = 11.8 min, major enantiomer (S) Rt = 16.6 min. The
absolute stereochemistry was assigned by comparison of the
retention times in HPLC and specific rotation signs with the litera-
ture data.2i,l The spectroscopic data were in agreement with the lit-
erature values.2i,l
The reaction mixture was purified using column chromatogra-
phy (silica gel, n-hexane/AcOEt, 7:1), and gave mainly the syn-iso-
mer in the first fraction (syn/anti 96:4 dr, 90% ee, 86 mg, 58% yield,
[a]
D = +5.5 (c 0.18, CH2Cl2). The anti-isomer was isolated in the
third fraction (syn/anti 5:95 dr, 97% ee, 17 mg, 12% yield).
4.2.9. 3,3-Dimethyl-1-nitrobutan-2-ol
The enantiomeric excess was determined by HPLC (Chiralpak
OD-H), hexane/i-PrOH 95:5, 1.0 mL/min, k = 210 nm, minor enan-
tiomer (R) Rt = 16.2 min, major enantiomer (S) Rt = 18.3 min. The
absolute stereochemistry was assigned by comparison of the
retention times in HPLC and specific rotation signs with the litera-
ture data.2g,l,8 The spectroscopic data were in agreement with the
literature values.2d,l
4.2.13.2.
Solidified yellow oil, [
anti-(1S,2R)-1-(Anthracene-9-yl)-2-nitrobutan-1-ol.
D = +16.2 (c 0.11, CH2Cl2, 97% ee); 1H
a]
NMR (300 MHz, CDCl3) d 1.04 (t, J = 7.3 Hz, 3H, CH3), 2.39–2.54
(m, 2H, CH2CH3), 2.78 (br s, 1H, OH), 5.36 (dt, J = 10.7, 3.3 Hz, 1H,
CHNO2), 6.60 (d, J = 7.4 Hz, 1H, CHOH), 7.46–7.59 (m, 4H, ArH),
8.02 (d, J = 8.4 Hz, 2H, ArH), 8.47 (s, 1H, ArH), 8.48–8.58 (m, 2H,
ArH).
4.2.10. 2-Nitro-1-phenylpropan-1-ol
Acknowledgments
Chiralpak AD-H, n-hexane/i-PrOH 95:5, 1 mL/min, k = 225 nm,
antimajor (1S,2R) Rt = 13.0, antiminor (1R,2S) Rt = 14.5, synmajor
(1S,2S) Rt = 17.9, synminor (1R,2R) Rt = 19.9 min.
We are grateful to the Polish Ministry of Science and Higher
Education for financial support, Grant No. N204 161036.

_
´
355
M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 22 (2011) 351–355
3. For functionalized Cinchona alkaloids used as organocatalysts for the
asymmetric Henry reaction, see: (a) Marcelli, T.; van der Haas, R. N. S.; van
Maarseveen, J. H.; Hiemstra, H. Synlett 2005, 2817–2819; (b) Marcelli, T.; van
der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed.
2006, 45, 929–931; (c) Marcelli, T.; Hiemstra, H. Synthesis 2010, 8, 1229–1279.
4. For recent examples, see: (a) Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.;
Strohmann, C. Chem. Eur. J. 2009, 15, 12764–12769; (b) Kowalczyk, R.;
References
1. For reviews on asymmetric nitroaldol reactions, see: (a) Palomo, C.; Oiarbide,
M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442–5444; (b) Boruwa, J.; Gogoi,
N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry 2006, 17, 3315–3326; (c)
Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561–2574.
2. For some latest examples of the asymmetric nitroaldol reaction, see: (a) Arai,
T.; Yokoyama, N.; Yanagisawa, A. Chem. Eur. J. 2008, 14, 2052–2059; (b) Blay,
G.; Hernandez-Olmos, V.; Pedro, J. R. Org. Biomol. Chem. 2008, 6, 468–476; (c)
Arai, T.; Yokoyama, N. Angew. Chem., Int. Ed. 2008, 47, 4989–4992; (d) Liu, S.;
Wolf, C. Org. Lett. 2008, 10, 1831–1834; (e) Lai, G.; Wang, S.; Wang, Z.
Tetrahedron: Asymmetry 2008, 19, 1813–1819; (f) Bulut, A.; Aslan, A.; Dogan, O.
J. Org. Chem. 2008, 73, 7373–7375; (g) Kowalczyk, R.; Sidorowicz, Ł.;
_
Skarzewski, J. Tetrahedron: Asymmetry 2009, 20, 2467–2473; (c) Luo, M.; Yan,
B. Tetrahedron Lett. 2010, 51, 5577–5580; (d) Khan, N. H.; Prasetyanto, E. A.;
Kim, Y.-K.; Ansari, M. B.; Park, S.-E. Catal. Lett. 2010, 140, 189–196; (e) See Refs.
2o,q–s,w.
5. (a) Misumi, Y.; Bulman, R. A.; Matsumoto, K. Heterocycles 2002, 56, 599–605;
(b) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732–733; (c) Knudsen,
K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362–1364.
_
Skarzewski, J. Tetrahedron: Asymmetry 2008, 19, 2310–2315; (h) Bandini, M.;
6. (a) Rey, N. A.; dos Santos, K. C.; Menezes, M. Â. B. C.; Mangrich, A. S.; Pereira-
Maia, E. C. J. Braz. Chem. Soc. 2006, 17, 497–504; (b) Tsangaris, J. M.; Kabanos, T.
H. A. Monatsh. Chem. 1982, 113, 1393–1398; (c) Wesełucha-Birczyn´ ska, A.;
Sinisi, R.; Umani-Ronchi, A. Chem. Commun. 2008, 4360–4362; (i) Nitabaru, T.;
Kumagai, N.; Shibasaki, M. Tetrahedron Lett. 2008, 49, 272–276; (j) Blay, G.;
Domingo, L. R.; Hernandez-Olmos, V.; Pedro, J. R. Chem. Eur. J. 2008, 14, 4725–
4730; (k) Kowalczyk, R.; Kwiatkowski, P.; Skarzewski, J.; Jurczak, J. J. Org. Chem.
2009, 74, 753–756; (l) Zielinska-Błajet, M.; Skarzewski, J. Tetrahedron:
´
Oleksyn, B. J.; Hoffmann, S. K.; Sliwin´ ski, J.; Borze˛cka-Prokop, B.; Goslar, J.;
_
Hilczer, W. Inorg. Chem. 2001, 40, 4526–4533; (d) Hilliard, H. M.; Axtell, D. D.;
_
´
Gilbert, M. M.; Yoke, J. T. J. Inorg. Nucl. Chem. 1969, 31, 2117–2121.
Asymmetry 2009, 20, 1992–1998; (m) Spangler, K. Y.; Wolf, C. Org. Lett. 2009,
11, 4724–4727; (n) Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 13860–13869; (o) Selvakumar, S.;
Sivasankaran, D.; Singh, V. K. Org. Biomol. Chem. 2009, 7, 3156–3162; (p) Cheng,
L.; Dong, J.; You, J.; Gao, G.; Lan, J. Chem. Eur. J. 2010, 16, 6761–6765; (q) Xu, H.;
Wolf, C. Chem. Commun. 2010, 8026–8028; (r) Xu, H.; Wolf, C. Synlett 2010,
2765–2770; (s) Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org.
Chem. 2010, 75, 1313–1316; (t) Steurer, M.; Bolm, C. J. Org. Chem. 2010, 75,
3301–3310; (u) Mayani, V. J.; Abdi, S. H. R.; Kureshy, R. I.; Khan, N.-U. H.; Das,
A.; Bajaj, H. C. J. Org. Chem. 2010, 75, 6191–6195; (v) Lang, K.; Park, J.; Hong, S. J.
Org. Chem. 2010, 75, 6424–6435; (w) Jin, W.; Li, X.; Huang, Y.; Wu, F.; Wan, B.
Chem. Eur. J. 2010, 16, 8259–8261; (x) Arai, T.; Taneda, Y.; Endo, Y. Chem.
Commun. 2010, 46, 7936–7938.
_
´
7. Zielinska-Błajet, M.; Kucharska, M.; Skarzewski, J. Synthesis 2006, 1176–1182.
8. Evans, D. A.; Seidel, D.; Rueping, M.; Lam, W. H.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2003, 125, 12692–12693.
_
9. Kowalczyk, R.; Sidorowicz, Ł.; Skarzewski, J. Tetrahedron: Asymmetry 2007, 18,
2581–2586.
10. (a) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 2894–
2897; (b) Sohtome, Y.; Takemura, N.; Takada, K.; Takagi, R.; Iguichi, T.;
Nagasawa, K. Chem. Asian J. 2007, 2, 1150–1160; (c) Uraguchi, D.; Sakaki, S.;
Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392–12393; (d) Arai, T.; Takashita, R.;
Endo, Y.; Watanabe, M.; Yanagishawa, A. J. Org. Chem. 2008, 73, 4903–4906; (e)
Toussaint, A.; Pfaltz, A. Eur. J. Org. Chem. 2008, 4591–4597.