Enantioselective nitro-Michael reactions catalyzed by short peptides on water

Article abstract of DOI:10.1039/b910249c

Simple unmodified N-proline-based di- and tripeptides in combination with sodium hydroxide additive catalyze the asymmetric Michael reaction of ketones with nitroolefins to furnish the corresponding γ-nitroketones with up to 99% yield, 99:1 dr and 70% ee

Full text of DOI:10.1039/b910249c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective nitro-Michael reactions catalyzed by short peptides on water†
Matthias Freund, Sebastian Schenker and Svetlana B. Tsogoeva*
Received 26th May 2009, Accepted 17th July 2009
First published as an Advance Article on the web 14th August 2009
DOI: 10.1039/b910249c
Simple unmodified N-proline-based di- and tripeptides in combination with sodium hydroxide additive
catalyze the asymmetric Michael reaction of ketones with nitroolefins to furnish the corresponding
g-nitroketones with up to 99% yield, 99:1 dr and 70% ee at room temperature and on water without any
organic cosolvent.
Introduction
Catalytic asymmetric reactions that can be performed in or on
water are of current interest, because water is cheap, safe, and
unique reactivity and selectivity are often observed when water
1-3
is used as a solvent. In recent years, increasing attention has
4
been paid to asymmetric organocatalytic reactions in aqueous
3
m,n,5-8
media.
Until recently, important contributions were made for
5
6
some C–C bond formation reactions—aldol, Mannich, Diels–
7
8
Alder and Michael reactions—using water as a solvent.
Michael reactions, in particular, have in recent years been the
subject of numerous advances aimed at the discovery of efficient
chiral organocatalysts and prominent examples of water-tolerant
organocatalysts have also been noted for this reaction.
Fig. 1
9
8
Since in our previous work on primary amine-thiourea catalyzed
While chiral pyrrolidine derivatives have been designed for
Michael reactions under aqueous conditions, surprisingly, no
nitro-Michael reactions, an improved performance was displayed
8
14
when AcOH/H
2
O was used as an additive, we carried out a
report is known on proline-based short peptides, catalyzing such
reactions on water and without the addition of any organic
further experiment with peptide 1 on water and in the presence of
30 mol% of AcOH. However, while H-Pro-Phe-OH (1) has now
been dissolved, it still showed no activity under these conditions
(entry 2, Table 1). Interestingly, changing the acidic additive to
the basic one (NaOH, 30 mol%) led to a full conversion after
17 hours (entry 3, Table 1). We were pleased to see that the peptide
has been dissolved very fast in the presence of NaOH and the
reaction worked well to afford the product in high yield (99%),
diastereoselectivity (95:5) and good enantioselectivity (68% ee).
When brine was used instead of water, the reaction was slow (57%
yield after 27 h) and the enantioselectivity decreased (12% ee,
entry 4).
Phosphate buffer solutions with pH 7 and 10, respectively, were
further used as a reaction medium. A buffer solution at pH 10 gave
better results, but did not provide an equally good stereoselectivity
and yield of the reaction, as was obtained on water with NaOH as
an additive (entries 5 and 6 vs. entry 3, Table 1).
10
cosolvents. However, features such as straightforward accessi-
bility from Nature’s toolbox and modularity render unmodified
peptidic catalysts with an enzyme-like character attractive alter-
11
natives to other organocatalysts.
Herein, we describe a first study of unmodified proline-based di-
and tripeptides as enantioselective catalysts for Michael additions
of ketones to nitrostyrenes on water, providing access to valuable
12
building blocks—g-nitroketones.
Results and discussion
Initially, we examined the nitro-Michael reaction of cyclohexanone
6) with trans-b-nitrostyrene (5) in the presence of short peptides
(
1
–4 (Fig. 1), easily prepared from readily available a-amino acids
10a,13
using standard procedures of peptide chemistry.
Next, other short peptides 2–4 were tested on water with NaOH
additive. Dipeptide H-Phe-Tyr-OH (2) containing a C-terminal
tyrosine moiety also mediated the asymmetric nitro-Michael reac-
tion, but surprisingly, with lower yield (36%) and stereoselectivity
First, we tested the catalytic activity of dipeptide H-Pro-Phe-
OH (1) under various conditions. Such a reaction failed when
carried out on water without any additives (entry 1, Table 1).
(88:12 dr and 61% ee) than the corresponding peptide with
C-terminal phenylalanine (entry 7 vs. entry 3, Table 1). Interest-
ingly, H-Pro-Val-OH (3) catalyzed the asymmetric formation of
7 in 71% yield, with 93:7 dr and 66% ee. Thus, while the yield
decreased, the stereoselectivity of this reaction remained nearly
unchanged when going from C-terminal phenylalanine to valine
Department of Chemistry and Pharmacy, Institute of Organic Chemistry
1
, University of Erlangen-Nuremberg, Henkestrasse 42, 91054, Erlangen,
Germany. E-mail: tsogoeva@chemie.uni-erlangen.de; Fax: +49-9131-85-
2
6865; Tel: +49-9131-85-22541
†
Electronic supplementary information (ESI) available: NMR spectra of
catalysts and catalytic products and HPLC chromatograms of the catalytic
products in comparison with authentic racemic compounds. See DOI:
(cf. entries 3 and 8), showing the beneficial effect of the neutral
1
0.1039/b910249c
side chains (L-Phe and L-Val) compared to the functionalized
This journal is © The Royal Society of Chemistry 2009
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Table 1 Michael addition of cyclohexanone to trans-b-nitrostyrene catalyzed by peptides 1–4 on water and/or aqueous media
a
b
c
Entry
Catalyst (mol%)
Additive (mol%)
Solvent
Time (h)
Yield (%)
syn:anti
ee (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
1 (30)
—
H
H
H
2
2
2
O
O
O
360
408
17
27
312
96
15
15
15
16
18
16
72
144
264
17
17
15
n.r.
n.r.
99
—
—
—
—
68
12
54
61
61
66
56
67
44
54
63
59
—
—
23
—
—
1 (30)
AcOH (30)
NaOH (30)
NaOH (30)
—
1 (30)
95:5
92:8
94:6
94:6
88:12
93:7
96:4
94:6
94:6
93:7
94:6
92:8
—
1 (30)
brine
PB / pH 7
PB / pH 10
57
d
1 (30)
40
77
36
71
70
80
75
71
80
72
trace
n.r.
52
43
n.r.
d
1 (30)
—
2 (30)
NaOH (30)
NaOH (30)
NaOH (30)
LiOH (30)
KOH (30)
H
H
H
H
H
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
O
O
3 (30)
4 (30)
1
1
1
1
1
1
1
1
1
1
1 (30)
1 (30)
1 (30)
Li
2
CO
3
(30)
1 (30)
NMM (30)
NaOH (10)
NaOH (5)
—
NaOH (30)
NaOH (30)
—
1 (10)
1 (5)
L-Pro (30)
L-Pro (30)
—
—
86:14
n.d.
—
AcONa (30)
15
a
c
b
Yields of isolated products after column chromatography. Determined by chiral-phase HPLC analysis (Daicel Chiralpak IA) of the crude product.
Enantioselectivities were determined for syn-product by chiral-phase HPLC analysis (Daicel Chiralpak IA) in comparison with authentic racemic
d
material. PB: phosphate buffer. n.r. = no reaction, n.d. = not determined, NMM = N-methylmorpholine.
residue (L-Tyr). Furthermore, the tripeptide H-Pro-Phe-Phe-OH
4) mediated the asymmetric assembly of product 7 in 70% yield
the second amino acid moiety (e.g. Phe) for high yield and good
stereoselectivity.
(
with 96:4 dr and 56% ee (Table 1, entry 9). The size of the small
peptide seems to be important for this transformation on water,
since the yield and the enantioselectivity of the Michael reaction
decreased with an additional C-terminal phenylalanine residue
Interestingly, while the use of NaOH alone provided the Michael
product with 43% yield, no reaction progress was detected with
the salt AcONa (entries 18 and 19, Table 1). This observation
implies that the influence of background reaction on the product
yield and enantioselectivity in the H-Pro-Phe-OH/NaOH (1:1)
catalyzed Michael reaction might be tiny (provided that any excess
of NaOH is excluded).
(
cf. entry 3 and 9).
Apart from NaOH, we were interested in trying out other
additives: LiOH, KOH, Li
2
CO and NMM. It can be seen in
3
Table 1 that addition of 0.3 equiv of NaOH gave the best
results concerning chemical yield, dr and ee (entry 3 vs. entries
We next probed the scope of the reaction for different aromatic
nitroolefins and Michael donors with selected dipeptide catalyst
and additive (H-Pro-Phe-OH/NaOH) on water and the results
are shown in Table 2. In all cases, reactions afforded syn-
products. 2-Furyl-1-nitroethene underwent clean reaction with
cyclohexanone affording the desired product in high yields and
diastereoselectivity, but lower enantioselectivity as compared to
trans-b-nitrostyrene (entry 1 vs. entry 2, Table 2). Interestingly,
while only little effect on the stereoselectivity was observed, the
yield decreased significantly when tetrahydrothiopyran-4-one was
used instead of cyclohexanone in the reaction with b-nitrostyrene
(entry 1 vs. entry 3, Table 2).
Both electron-rich and electron-deficient nitrostyrenes were
shown to be good Michael acceptors for cyclohexanone and the
reactions all occurred smoothly on water (Table 2, entries 4–7).
The desired Michael products were obtained in good to high yields
(75–96%) and showed excellent diastereoselectivities (syn:anti up
to 99:1) and good enantioselectivities (58–70%).
1
0–13). Comparable diastereoselectivities and enantioselectivities,
although slightly lower yields, were obtained with LiOH and
NMM (entries 10 and 13 vs. entry 3). Additionally, NMM required
longer time for completion. KOH and Li
2
CO gave lower yields
3
and enantioselectivities (entries 11 and 12 vs. entry 3). Thus, we
found that addition of 0.3 equiv of NaOH furnished the best
results.
Next, we investigated the influence of the catalyst and additive
loadings on the reaction outcome. A reduction in the amount
of catalyst 1 and additive (NaOH) to 10 mol% resulted in a
relatively slow reaction and still gave 72% yield, 92:8 dr and 59%
ee within 144 h (Table 1, entry 14). No conversion was observed
in the presence of 5 mol% of dipeptide 1 and additive (entry 15).
Therefore we used 30 mol% of the combination dipeptide 1 and
sodium hydroxide in further studies.
Also the potential of L-proline have been tested on water. While
no reaction progress was detected after 17 hours in the presence
of 30 mol% of L-proline, moderate yield (52%), good dr (86:14)
and low enantioselectivity (23% ee) were observed with NaOH
additive (entries 16 and 17), demonstrating the importance of
An acyclic ketone donor—acetone—has also been tested under
the previously optimized conditions but with less success. The
reaction of acetone with trans-b-nitrostyrene (5) resulted in
product with 23% yield and 20% ee.
4
280 | Org. Biomol. Chem., 2009, 7, 4279–4284
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Table 2 Examples of H-Pro-Phe-OH catalyzed nitro-Michael additions
of different ketones to nitroolefins on water
a
b
c
Entry Time (h)
Product
Yield (%)
99
syn:anti
ee (%)
68
1
17
95:5
Fig. 2 Proposed transition state for the nitro-Michael reaction catalyzed
-
+
by the salt H-Pro-Phe-O Na on water.
amide NH and strengthen the related hydrogen bond with the nitro
group of the trans-b-nitrostyrene. The additional positive effect of
water could be ascribed to the hydrogen bonds formed between the
nitro-group and a water molecule, which at the same time forms
the hydrogen bond with the COO group of the catalyst, thus,
stabilizing the transition state.
2
3
26
17
92
65
97:3
94:6
41
59
-
Conclusion
In summary, we have demonstrated for the first time that short un-
modified peptides in combination with basic additives (e.g. H-Pro-
Phe-OH/NaOH) can catalyze asymmetric nitro-Michael addition
reactions of ketones to nitroolefins on water without addition of
organic cosolvents, giving good reactivity and stereoselectivity (up
to 99% yield, 99:1 dr and 70% ee).
Further studies of short peptide-catalyzed C–C bond-forming
reactions on water and DFT calculations on the mechanism of
this peptide–aqueous media system are currently underway and
will be reported in due course.
4
5
6
7
28
17
48
16
89
78
75
96
92:8
92:8
95:5
99:1
66
70
58
64
Experimental
General information
All commercially available reagents were used without purification
and solvents were distilled prior to column chromatography.
Optical rotations were measured with PerkinElmer 341. NMR
spectra were recorded with Bruker Avance 300. Because of a
better solubility, all peptides were measured as hydrochlorides. J
values are given in Hz. FAB mass spectra were measured with
a Micromass: ZabSpec, MALDI mass spectra were recorded
with a Shimadzu Biotech AXIMA Confidence spectrometer. The
enantiomeric and diastereomeric excess of products was deter-
mined by chiral HPLC analysis (using column Chiralpak IA)
in comparison with authentic racemic material. Relative (syn)
and absolute configuration of the known products 7–14 was
determined by comparison with literature data. HPLC mea-
surements were performed using Agilent 1200 Series enginery:
Vacuum Degasser G1322-90010, Quaternary Pump G1311-90010,
Thermostated Column Compartment G1316-90010, Diode Array
and Multiple Wavelength Detector SL G1315-90012, Standard and
Preparative Autosampler G1329-90020 and Agilent Chemstation
for LC software.
8
17
23
—
20
a
b
c
2
Yield of isolated product after column chromatography on SiO .
Determined by chiral HPLC analysis (Daicel Chiralpak IA, see ESI†).
Enantioselectivities were determined by chiral HPLC analysis in compar-
ison with authentic racemic material (Daicel Chiralpak IA, see ESI).
15a,b
25
The stereoselectivities observed and the possible role of water
we rationalized by means of the assumed transition state depicted
in Fig. 2. The hydrogen bond between a water molecule and the
amide oxygen atom of the peptide could increase the acidity of the
(S)-Prolyl-(S)-phenylalanine (H-Pro-Phe-OH) (1)
-36.1 (c = 1, 1 N aq. HCl); NMR of H-Pro-Phe-OH·HCl:
(300 MHz; DMSO[d6]) 1.69–1.95 (3 H, m, CH Pro), 2.17–
2.39 (1 H, m, CH Pro), 2.93 (1 H, dd, J 9.4 and 13.9, CH Phe),
.
[a]
D
d
H
2
2
2
This journal is © The Royal Society of Chemistry 2009
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1
4a,16a,16d
3
.12 (1 H, dd, J 4.6 and 13.9, CH
Pro), 4.07–4.26 (1 H, m, a-CH Pro), 4.46 (1 H, ddd, J 4.6, 7.8 and
.4, a-CH Phe), 7.16–7.34 (5 H, m, C Phe), 8.47 (1 H, br s,
NH), 9.05 (1 H, d, J 7.8, NH), 10.27 (1 H, br s, NH) and 12.86
1 H, br s, CO H); d (300 MHz; DMSO[d6]) 23.76, 30.09, 36.55,
5.86, 54.45, 58.72, 126.90, 128.62, 129.47, 137.78, 168.67 and
2
Phe), 3.01–3.31 (2 H, m, CH
2
2-(2-Nitro-1-phenyl-ethyl)-cyclohexanone
(7)
.
d
H
(300 MHz; DMSO[d6]) 1.04–1.22 (1 H, m), 1.41–1.79
9
6
H
5
(4 H, m), 1.88–2.06 (1 H, m), 2.21–2.55 (2 H, m), 2.75–2.93
(1 H, m), 3.72 (1 H, ddd, J 3.8, 4.6 and 10.7), 4.81 (1 H, dd,
J 10.7 and 13.0), 5.00 (1 H, dd, J 4.6 and 13.0) and 7.21–7.44
(
2
C
4
1
(5 H, m); d
C
(300 MHz; DMSO[d6]) = 24.72, 28.29, 32.69, 42.45,
+
72.60; m/z (FAB) 263 (MH , 100%), 154 (17%) and 136 (13%).
43.76, 51.75, 79.19, 127.59, 128.75, 128.83, 138.74 and 211.96;
Chiral HPLC (Chiralpak IA, 2-PrOH/hexane 3:97, 1.00 ml/min,
1
5a
25
(
S)-Prolyl-(S)-tyrosine (H-Pro-Tyr-OH) (2)
c = 2, 3 N aq. HCl); NMR of H-Pro-Tyr-OH·HCl: d
O) 1.78–2.09 (3 H, m, CH Pro), 2.23–2.42 (1 H, m, CH
.90 (1 H, dd, J 9.1 and 14.0, CH Tyr), 3.09 (1 H, dd, J 5.8
and 14.0, CH Tyr), 3.19–3.42 (3 H, m, CH Pro, C OH Tyr),
.17–4.33 (1 H, m, a-CH Pro), 4.55 (1 H, dd, J 5.8 and 9.1, a–CH
Tyr), 6.77 (2 H, d, J 8.3, 4-HO-C Tyr) and 7.08 (2 H, d, J 8.6,
O) 23.12, 29.13, 34.90, 45.99,
2.42, 54.09, 58.91, 114.87, 127.68, 129.95, 153.90, 168.75, 172.57
.
[a]
(300 MHz;
Pro),
D
-27.5
◦
2
1
10 nm, 25 C): t
7.4 min (anti) and 20.0 min (anti).
R
15.9 min (minor syn), 20.9 min (major syn),
(
D
2
H
2
2
2
2
16b,16d
2
-(1-Furan-2-yl-2-nitro-ethyl)-cyclohexanone
300 MHz; CDCl ) 1.12–1.31 (1 H, m), 1.43–1.83 (4 H, m),
.94–2.10 (1 H, m), 2.22–2.45 (2 H, m), 2.59–2.78 (1 H, m), 3.40
(8)
.
d
H
2
2
6
H
4
(
1
3
4
6
H
4
(
(
1 H, ddd, J 4.8, 4.8 and 9.3), 4.59 (1 H, dd, J 9.3 and 12.5), 4.72
1 H, dd, J 4.8 and 12.5), 6.11 (1 H, dd, J 0.6 and 3.2), 6.21 (1 H,
4
5
-HO-C
6
H
4
Tyr); d
C
(300 MHz; D
2
dd, J 1.9 and 3.2) and 7.27 (1 H, dd, J 0.6 and 1.9); d
C
(300 MHz;
+
+
and 173.83; m/z (MALDI) 279 (MH , 100%) and 301 (MNa ,
CDCl ) 25.50, 28.62, 32.89, 37.05, 42.97, 51.46, 77.06, 109.39,
3
2
5%).
1
2
10.72, 142.74, 151.31 and 211.37; Chiral HPLC (Chiralpak IA,
◦
-PrOH/hexane 10:90, 1.00 ml/min, 210 nm, 25 C): t
R
9.0 min
1
5c,d
25
(
S)-Prolyl-(S)-valine (H-Pro-Val-OH) (3)
, MeOH/concentrated aq. HCl 10:1); NMR of H-Pro-Val-
(300 MHz; DMSO[d6]) 0.91 (6 H, d, J 6.7, CH(CH
Val), 1.74–1.83 (3 H, m, CH Pro), 2.02–2.18 (1 H, J 5.5 and 6.7,
CHCH(CH Val), 2.22–2.41 (1 H, m, CH Pro), 3.07–3.28 (2 H,
m, CH Pro), 4.16 (1 H, dd, J 5.5 and 8.1, a-CH Val), 4.24–4.37
1 H, m, a-CH Pro), 8.54 (1 H, br s, NH), 8.74 (1 H, d, J 8.1, NH),
H); d (300 MHz;
DMSO[d6]) 17.82, 19.08, 23.41, 29.48, 29.81, 45.51, 57.70, 58.29,
68.55 and 172.22; m/z (FAB) 215 (MH , 100%).
.
[a]
D
-58.5 (c =
(
anti), 9.5 min (major syn), 10.8 min (anti) and 11.6 min (minor
1
syn).
OH·HCl: d
H
)
3 2
2
1
4a,16c,16d
3
-(2-Nitro-1-phenylethyl)-tetrahydro-thiopyran-4-one (9)
(300 MHz; CDCl ) 2.38 (1 H, dd, J 9.4 and 13.8), 2.53 (1 H,
ddd, J 1.5, 4.2 and 13.8), 2.64–3.03 (5 H, m), 3.91 (1 H, ddd, J 4.6,
.6 and 9.7), 4.55 (1 H, dd, J 9.7 and 12.6), 4.68 (1 H, dd, J 4.6
and 12.6) and 7.09–7.33 (5 H, m); d (300 MHz; CDCl ) 31.51,
5.03, 43.39, 44.46, 54.87, 78.53, 128.08, 128.19, 129.21, 136.42
.
3
)
2
2
d
H
3
2
(
1
4
0.33 (1 H, br s, NH) and 12.76 (1 H, br s, CO
2
C
C
3
3
+
1
and 209.44; Chiral HPLC (Chiralpak IA, 2-PrOH/hexane 15:85,
◦
0
.95 ml/min, 210 nm, 25 C): t
R
11.3 min (minor syn), 13.4 min
(
S)-Prolyl-(S)-phenylalanyl-(S)-phenylalanine (H-Pro-Phe-Phe-
15e
25
(anti), 21.4 min (anti) and 25.6 min (major syn).
OH) (4)
HCl 10:1); NMR of H-Pro-Phe-Phe-OH·HCl: d
DMSO[d6]) 1.40–1.90 (3 H, m, CH Pro), 1.93–2.37 (1 H, m,
CH Pro), 2.62–3.24 (6 H, m, 2 ¥ CH Phe and Pro), 4.08 (1 H, m,
a-CH Pro), 4.34–4.72 (2 H, m, a-CH Phe), 7.05–7.73 (10 H, m,
¥ C Phe), 8.39 (1 H, br s, NH), 8.53–9.12 (2 H, m, 2 ¥ NH)
and 10.32 (1 H, br s, CO H); d
(300 MHz; DMSO[d6]) = 23.38,
9.78, 36.46, 37.30, 45.47, 53.72, 54.54, 58.34, 126.34, 126.48,
.
[a]
D
-27.6 (c = 1, MeOH/concentrated aq.
H
(300 MHz;
16c,16d
2
-[1-(4-Chloro-phenyl)-2-nitro-ethyl]-cyclohexanone (10)
(300 MHz; CDCl ) 1.06–1.23 (1 H, m), 1.40–1.77 (4 H, m),
.95–2.07 (1 H, m), 2.22–2.45 (2 H, m), 2.51–2.64 (1 H, m), 3.69
.
2
d
1
H
3
2
2
(
1 H, ddd, J 4.5, 4.5 and 10.1), 4.52 (1 H, dd, J 10.1 and 12.6
2
6
H
5
Hz), 4.87 (1 H, dd, J 4.5 and 12.4), 7.05 (2 H, d, J 8.5 Hz) and
2
C
7
4
2
.22 (2 H, d, J 8.5); d
3.15, 43.75, 52.75, 79.01, 129.52, 129.97, 133.97, 136.70 and
C
(300 MHz; CDCl ) 25.46, 28.86, 33.58,
3
2
1
1
28.05, 128.11, 128.18, 129.15, 129.20, 129.25, 137.15, 137.46,
37.53, 137.56, 167.88, 170.65, 170.79, 171.66 and 172.62; m/z
MALDI) = 410 (MH , 81%) and 432 (MNa , 100%).
12.01; Chiral HPLC (Chiralpak IA, 2-PrOH/hexane 15:85, 0.95
◦
+
+
ml/min, 210 nm, 25 C): t 10.0 min (minor syn), 10.3 min (anti),
(
R
1
2.9 min (anti) and 13.6 min (major syn).
General and representative procedure for Michael additions of
cyclohexanone to trans-b-nitrostyrenes
1
6e
2
-[2-Nitro-1-(4-nitro-phenyl)-ethyl]-cyclohexanone (11)
.
d
H
(
300 MHz; CDCl ) 1.16–1.37 (1 H, m), 1.49–1.87 (4 H, m), 2.00–
3
The peptide catalyst (199.8 mmol, 0.3 eq) and sodium hydroxide
2.19 (1 H, m), 2.27–2.55 (2 H, m), 2.65–2.82 (1 H, m), 3.94 (1 H,
ddd, J 4.3, 4.4 and 10.0), 4.69 (1 H, dd, J 10.0 and 13.0), 5.01
(1 H, dd, J 4.4 and 13.0 Hz), 7.41 (2 H, d, J 8.8) and 8.19
(
199.8 mmol, 0.3 eq) were stirred in water (2.127 ml) for 15 min at
ambient temperature. Cyclohexanone (7.259 mmol, 10.9 eq) was
added and the reaction system was equilibrated for further 15 min.
Then the respective trans-b-nitrostyrene (667.0 mmol, 1.0 eq) was
added. The biphasic system was stirred vigorously, until thin
layer chromatography (petrol ether/ethyl acetate 6:1) indicated
complete consumption of the trans-b-nitrostyrene. By addition
of 1 N aqueous hydrochloric acid, the reaction mixture was
adjusted to pH 1, the product was extracted with dichloromethane
(2 H, d, J 8.8); d
C
(300 MHz; CDCl ) 25.50, 28.73, 33.61, 43.14,
3
44.13, 52.55, 78.40, 124.50, 129.75, 146.03, 147.80 and 211.36;
Chiral HPLC (Chiralpak IA, 2-PrOH/hexane 15:85, 0.95 ml/min,
◦
210 nm, 25 C): t
R
23.0 min (minor syn), 28.1 min (anti), 34.3 min
(anti) and 44.3 min (major syn).
16b,16d
2-[1-(4-Methoxy-phenyl)-2-nitro-ethyl]-cyclohexanone (12)
.
(
3 ¥ 20 ml), dried over MgSO
4
and evaporated. To purify the
d
H
(300 MHz; CDCl ) 1.06–1.23 (1 H, m), 1.40–1.77 (4 H, m),
3
product, flash chromatography over silica gel was applied (petrol
ether/ethyl acetate mixtures).
1.94–2.06 (1 H, m), 2.24–2.44 (2 H, m), 2.51–2.63 (1 H, m), 3.64
(1 H, ddd, J 4.6, 4.6 and 10.0), 3.70 (3 H, s), 4.50 (1 H, dd, J 10.0
4
282 | Org. Biomol. Chem., 2009, 7, 4279–4284
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View Article Online
and 12.3), 4.84 (1 H, dd, J 4.6 and 12.3), 6.77 (2 H, d, J 8.7) and
5 For organocatalytic aldol reactions, using water as a solvent, see:
(
a) S. S. Chimni and D. Mahajan, Tetrahedron, 2005, 61, 5019; (b) N.
7
.01 (2 H, d, J 8.7); d
C
(300 MHz; CDCl ) 24.94, 28.47, 33.08,
3
Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and C. F.
Barbas, III, J. Am. Chem. Soc., 2006, 128, 734; (c) Y. Hayashi, T.
Sumiya, J. Takahashi, H. Gotoh, T. Urushima and M. Shoji, Angew.
Chem., 2006, 118, 972; Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh,
T. Urushima and M. Shoji, Angew. Chem. Int. Ed., 2006, 45, 958; (d) Y.
Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya and M. Shoji,
Angew. Chem., 2006, 118, 5653; Y. Hayashi, S. Aratake, T. Okano,
J. Takahashi, T. Sumiya and M. Shoji, Angew. Chem. Int. Ed., 2006,
45, 5527; (e) Z. Q. Jiang, Z. A. Liang, X. Y. Wu and Y. X. Lu, Chem.
Commun., 2006, 2801; (f) Y. Y. Wu, Y. Z. Zhang, M. L. Yu, G. Zhao and
S. W. Wang, Org. Lett., 2006, 8, 4417; (g) D. Font, C. Jimeno and M. A.
Peric a` s, Org. Lett., 2006, 8, 4653; (h) V. Maya, M. Raj and V. K. Singh,
Org. Lett., 2007, 9, 2593; (i) N. Zotova;, A. Franzke, A. Armstrong
and D. G. Blackmond, J. Am. Chem. Soc., 2007, 129, 15100; (j) J. M.
Huang, X. T. Zhang and D. W. Armstrong, Angew. Chem. Int. Ed.,
4
2.66, 43.14, 52.59, 55.14, 79.04, 114.21, 129.10, 129.46, 158.92
and 212.03; Chiral HPLC (Chiralpak IA, 2-PrOH/hexane 15:85,
0
◦
.50 ml/min, 210 nm, 25 C): t
R
18.8 min (minor syn), 20.1 min
(
anti), 22.0 min (major syn) and 23.7 min (anti).
16b,16d
2
-(1-Naphth-2-yl-2-nitro-ethyl)-cyclohexanon
(13)
.
d
H
(300 MHz; CDCl
3
) 1.04–1.24 (1 H, m), 1.27–1.73 (5 H, m),
1
(
4
(
.85–2.06 (1 H, m), 2.18–2.46 (2 H, m), 2.58–2.79 (1 H, m), 3.85
1 H, ddd, J 4.4, 4.5 and 10.2), 4.62 (1 H, dd, J 10.2 Hz and 12.5),
.93 (1 H, dd, J 4.5 and 12.5), 7.15–7.24 (1 H, m), 7.32–7.44
2 H, m), 7.56 (1 H, s) and 7.64-7.78 (3 H, m); d (300 MHz;
) 25.42, 28.93, 33.75, 43.19, 44.51, 52.82, 79.29, 125.67,
C
CDCl
3
2
007, 46, 9073; (k) S. Aratake, T. Itoh, T. Okano, N. Nagae, T. Sumiya,
126.60, 126.87, 128.10, 128.23, 129.29, 133.22, 133.74, 135.55 and
M. Shoji and Y. Hayashi, Chem. Eur. J., 2007, 13, 10246; (l) X. Y. Wu,
Z. Q. Jiang, H. M. Shen and Y. X. Lu, Adv. Synth. Catal., 2007, 349,
812.
For examples of organocatalytic Mannich reactions, using water as a
solvent, see: (a) L. Cheng, X. Wu and Y. Lu, Org. Biomol. Chem., 2007,
2
12.37; Chiral HPLC (Chiralpak IA, 2-PrOH/hexane 15:85, 0.50
◦
ml/min, 210 nm, 25 C): t
syn) and 29.2 min (both anti).
R
24.3 min (minor syn), 27.3 min (major
6
7
5
, 1018; (b) Y. Hayashi, T. Urushima, S. Aratake, T. Okano and K.
14a,16f
5
-Nitro-4-phenyl-pentan-2-one (14)
.
d
H
(300 MHz;
Obi, Org. Lett., 2008, 10, 21; (c) Y.-C. Teo, J.-J. Lau and M.-C. Wu,
Tetrahedron: Asymmetry, 2008, 19, 186.
DMSO[d6]) 2.03 (3 H, s), 2.92 (2 H, d, J 7.1), 3.78–3.90 (1 H,
m), 4.77 (1 H, dd, J 9.4 and 12.9, 1H), 4.87 (1 H, dd, J 6.0 and
For examples of organocatalytic Diels–Alder reactions, using water as a
solvent, see: (a) A. B. Northrup and D. W. C. MacMillan, J. Am. Chem.
Soc., 2002, 124, 2458; (b) A. Y. Hayashi, S. Samanta, H. Gotoh and H.
Ishikawa, Angew. Chem. Int. Ed., 2008, 47, 6634; (c) Q. Xu, A.-B. Xia,
S.-P. Luo, J. Tang, S. Zhang, J.-R. Jiang and Z.-Y. Xu, Angew. Chem.
Int. Ed., 2009, 48, 3821.
1
2.9) and 7.21–7.36 (5 H, m); d
C
(300 MHz; DMSO[d6]) 29.98,
38.78, 45.59, 79.41, 127.13, 127.57, 128.42, 139.84 and 205.92;
Chiral HPLC (Chiralpak IA, 2-PrOH/hexane 3:97, 1.00 ml/min,
◦
2
10 nm, 25 C): t
R
16.5 min (S) and 17.6 min (R).
8
For examples of organocatalytic Michael reactions, using water as a
solvent, see: (a) N. Mase, K. Watanabe, H. Yoda, K. Takabe, F. Tanaka
and C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 4966; (b) A.
Corleone, M. Marigo, C. North, A. Landa and K. A. Jørgensen, Chem.
Commun., 2006, 4928; (c) L. Zu, J. Wang, H. Li and W. Wang, Org.
Lett., 2006, 8, 3077; (d) S. Z. Luo, X. L. Mi, S. Liu, H. Xu and J.-P.
Cheng, Chem. Commun., 2006, 3687; (e) Y.-J. Cao, Y.-Y. Lai, X. Wang,
Y.-J. Li and W.-J. Xiao, Tetrahedron Lett., 2007, 48, 21; (f) E. Alza,
X. C. Cambeiro, C. Jimeno and M. A. Peric a` s, Org. Lett., 2007, 9,
Acknowledgements
The authors gratefully acknowledge generous financial support
from the Deutsche Forschungsgemeinschaft (SPP 1179).
´
717; (g) C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente and
3
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284 | Org. Biomol. Chem., 2009, 7, 4279–4284
This journal is © The Royal Society of Chemistry 2009