Asymmetric conjugate addition of nitroalkanes to enones with a chiral α-aminophosphonate catalyst

Article abstract of DOI:10.1016/j.tetasy.2008.07.007

Chiral diethyl (2R)-tetrahydropyrro-2-ylphosphonate is an effective catalyst for the Michael addition of nitroalkanes to α,β-unsaturated ketones. This study revealed that the hydrate salt of this α-aminophosphonate was found to be a better catalytic speci

Full text of DOI:10.1016/j.tetasy.2008.07.007

Tetrahedron: Asymmetry 19 (2008) 1934–1940
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric conjugate addition of nitroalkanes to enones with a chiral
a-aminophosphonate catalyst
*
Marcus Malmgren, Johan Granander, Mohamed Amedjkouh
Department of Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral diethyl (2R)-tetrahydropyrro-2-ylphosphonate is an effective catalyst for the Michael addition of
nitroalkanes to ,b-unsaturated ketones. This study revealed that the hydrate salt of this -amino-
phosphonate was found to be a better catalytic species. Moderate to high enantioselectivities were
achieved in reactions that tolerate various nitroalkanes and enones in the presence of low loading of both
catalyst (10 mol %) and bulk base (25 mol %).
Received 18 June 2008
Accepted 4 July 2008
Available online 16 August 2008
a
a
Ó 2008 Published by Elsevier Ltd.
1. Introduction
to excellent enantioselectivities (61–93%), with the lower enanti-
oselectivity arising from the addition of the less bulky nitrometh-
The asymmetric conjugate addition of carbon nucleophiles to
electron-poor alkenes is among the most powerful transformations
for the formation of carbon–carbon bonds in organic synthesis.1
ane and nitroethane nucleophiles.
N
N
Owing to the hydrogen acidity at the
a-position, nitroalkanes
N
N
CO2H
(pKa MeNO2 = 10) are a particularly useful source of stabilized car-
banions2 for the asymmetric addition to electron-poor alkenes. In
addition, the nitro group represents a versatile functionality allow-
ing further chemical transformations into a variety of functionally
useful compounds. Thus, the asymmetric conjugate additions of
CO2H
Bn
Bn
N
H
N
H
N
H
N
HN
1
2
3
O
N
H
N
nitroalkanes to
a,b-unsaturated carbonyls remain the subject of
N
N
N
H
intense development. The most general systems reported to date
include metal-catalysts, for example, chiral crown ethers3 and
chiral Lewis acids.4 In addition, Jacobsen et al. have investigated
N
HN
N
N
H
5
4
the use of an aluminum–salen catalyst with
a,b-unsaturated
ketones other than chalcones, in high yields and in good to excel-
lent enantioselectivity.5 Recently, the field of organocatalysis has
been developing rapidly.6 Good results have been achieved with
chiral ammonium salts derived from cinchona alkaloids as phase-
transfer catalysts7 and cinchona alkaloid-derived thiourea cata-
lysts,8 however, only the reaction of chalcones with nitromethane
was explored. Yamaguchi et al. first employed iminium activation
in the asymmetric addition of 2-nitropropane to 2-cyclohexenone
Ar
Ar
PO(OEt)2
N
N
H
H•X
OTMS
7 X= –
6
8 X=H2O
Figure 1. Pyrrolidine-based catalysts.
in the presence of rubidium L
-prolinate.9 Thus, based on this strat-
Jørgensen et al. reported the catalytic asymmetric conjugate
addition of nitroalkanes to acyclic ,b-unsaturated enones in the
egy, several pyrrolidine-based catalysts have been successfully
applied to the Michael reaction of nitroalkanes (Fig. 1). Extensive
investigations revealed that piperazine bases provided the best
results when used as bulk bases in the presence of proline 1 for
additions to cyclic enones.10 Specifically, the reaction gave good
a
presence of imidazoline catalyst 2 with good enantioselectivities
(34–86%).11 However, only a moderate enantioselectivity (49%)
was obtained using cyclohexenone as the acceptor. In addition,
reaction times between 4.5 and 12.5 days required the nitroalk-
anes to be employed as the reaction solvent (ꢀ20-fold excess). La-
ter, the same group described the tetrazole analogue 3, which led
to improved enantioselectivities and rates under similar reaction
* Corresponding author. Tel.: +46 31 772 2895; fax: +46 31 772 3840.
E-mail address: mamou@chem.gu.se (M. Amedjkouh).
0957-4166/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2008.07.007

M. Malmgren et al. / Tetrahedron: Asymmetry 19 (2008) 1934–1940
1935
conditions (3–8 days).12 Interestingly, 4-trans-amino-proline-
based di- and tetrapeptides, in the presence of trans-2,5-dimethyl-
piperazine, successfully catalyzed the enantioselective conjugate
addition of nitroalkanes to cyclic enones with up to 88% ee.13 The
effectiveness of the tetrazole catalyst 4 was demonstrated for the
asymmetric addition of a variety of nitroalkanes to both cyclic
and acyclic enones using trans-2,5-dimethylpiperazine as a stoichi-
ometric base additive. Reactions with 4 provided enantiomeric ex-
cesses of up to 98% in relatively short reaction times of 1–3 days.14
deprotonate the nitroalkane yet one that does not catalyze the
Michael addition. For comparison with literature data a base
concentration of 1 M was used in dichloromethane as the solvent.
All reactions were performed at room temperature for 26 h and
then quenched with saturated NH4Cl, and analyzed on chiral GC
(Table 1).
Table 1
Base-catalyzed background reaction
For a,b-unsaturated aldehydes, Maruoka’s chiral phase transfer
Base
Conversion (%)
catalyst was successful in the Michael addition of silyl nitronates.15
More recently, Arvidsson et al. reported the Michael reaction of
enals with nitroalkanes catalyzed by imidazole-containing organo-
catalyst 5. The authors’ strategy was aimed at incorporating both
the iminium-activating function and the base in the catalyst.16
Later, Hayashi et al. reported a similar reaction using diphenylpro-
linol silyl ether 6 as an organocatalyst.17 This reaction expanded
upon the previous substrate scope and involves the successful
Piperazine
Morpholine
TMEDA
DMEDA
Ethylendiamine
Pyrrolidine
Triethylamine
DBU
2,5-trans-Dimethylpiperazine
27
13 (87% amine addition)
0
85
86
100
5
100
4
reaction of nitromethane directly with a,b-unsaturated aldehydes.
Despite the progress in the asymmetric addition of nitroalkanes to
enones, catalysis with proline derivatives requires substantial
amounts of base, 1 equiv with respect to enone substrate, and
often with a relatively high catalyst loading of 20 mol % to effect
the reaction in a reasonable timescale.
Typically, a negligible competitive background reaction was ob-
served when triethylamine, TMEDA, and trans-2,5-dimethylpipera-
zine were used as bases in the absence of catalyst 8. Surprisingly,
piperazine furnished 27% of the background racemic product 9.
In the literature, piperazine and trans-2,5-dimethylpiperazine have
proven to be the most effective bases for proline and the pyrroli-
dine-tetrazole catalyst.10,14 Interestingly, piperazine and trans-
2,5-dimethylpiperazine in the presence of catalyst 8 provided an
er of 82:18 and 84:16, respectively. Herein, morpholine was an
exception, and proved to act readily as a Michael donor to yield
87% of the addition product.
Herein, we report the use of
a
-aminophosphonate 7,18 in
conjunction with an appropriate acid co-catalyst to promote the
Michael addition of nitroalkanes to enones. Judicious choice of a
proton source has implications for higher reactivity although with
marginal effect on the selectivity. With some substrates, the cata-
lytic system (10 mol %) still operates efficiently at catalytic concen-
tration of bulk base.
2.2. Base concentration
2. Results and discussion
The concerns raised by a measurable background reaction even
with the remarkably effective trans-2,5-dimethylpiperazine
prompted us to question the concentration of bulk base used in
the Michael addition of nitroalkanes. The asymmetric Michael
addition of nitroalkanes, in most cases, still requires 100–
150 mol % of bulk base to achieve good conversion. Hence, the
amount of bulk base was varied for the purpose of this study. It
An initial evaluation of a-aminophosphonate 7 as a catalyst was
performed using achiral meso base trans-2,5-dimethylpiperazine,
under conditions similar to those developed earlier by Hanessian
and Pham . It was encouraging to see that reacting cyclohexenone
with 2-nitropropane (1.5 equiv) in the presence of trans-2,5-
dimethylpiperazine (1 equiv) and aminophosphonate (10 mol %)
at room temperature in THF, afforded the desired product (R)-9
in good yields with enantioselectivities up to 89:11 er (Scheme 1).
Interestingly, during these preliminary investigations we noticed a
change in the structure of catalyst 7, which also induced a variation
in the reaction rate. Freshly prepared 7 was isolated as a yellow oil
that crystallized upon standing. This solid was identified as
hydrate product 8 and displayed higher reactivity with similar
enantioselectivity (vide infra).
is noteworthy that in the addition reaction catalyzed by
8
(10 mol %), base loading was successfully reduced to 25 mol % with
respect to the enone substrate and had little effect on the
enantioselectivity (see Fig. 2).
100
95
90
85
O
80
75
70
O
7 or 8 (10 mol%)
Base 1 equiv.
NO2
+
O2N
ee
65
60
THF, rt
conv.
9
55
50
Scheme 1. Michael addition catalyzed by aminophosphonate 7 or 8.
25
50
100
mol% base
2.1. Screening for base: investigation of background reaction
Figure 2. Effect of base concentration.
Our initial investigation into the Michael addition of 2-nitropro-
pane began with the evaluation of a wide range of bases, provided
that the added base could lead to parallel non-selective reactions.
Thus, a screening of the base-catalyzed background reaction was
carried out, with the objective of finding a strong enough base to
2.3. Effect of solvent
The solvent has proven to be very important for stereoselectiv-
ity in organocatalytic reactions. Therefore, using conditions similar

1936
M. Malmgren et al. / Tetrahedron: Asymmetry 19 (2008) 1934–1940
Table 2
co-catalysts. In an effort to improve the Michael adduct yield with-
Effect of solventa
out a loss of the favorable selectivities, we examined a range of
proton sources for the formation of complexes 7ꢁHX as catalysts
for the model reaction (Table 3).
O
O
8 (10 mol%)
Base (25 mol%)
NO2
+
O2N
Table 3
Solvent, rt
The effects of proton source and counterion on the model reaction
9
Acida
Time
Conversionb (%)
er 9 (%)
Solvent
Conversion (%)
er 9 (%)
Entry
CHCl3
THF
EtOH
Toluene
DMSO
DMF
96
98
99
98
99
93
87
96
90
85
100
91
99
100
100
87:13
89:11
57:43
84:16
54:46
77:23
85:15
83:17
88:12
87:13
64:36
83:17
76:24
70:30
47:53
1
2
3
4
5
6
7
— (7)
H2O (8)
6 days
2 days
22 h
5 days
6 days
11 days
12 days
98
97
88
93
95
97
99
89:11
87:13
89:11
90:10
90:10
92:8
p-NO2PhOH (10)
HCl (11)
HOAc (12)
H3PO4 (13)
p-TsOH (14)
DEE
85:15
MTBE
Dioxane
DME
Hexane
MeCN
t-amylOH
i-PrOH
MeOH
a
Used to form salt with 7.
Standard conditions were used, that is, 10 mol % 7, 25 mol % trans-2,5-
b
dimethylpiperazine, and 1.5 equiv nitroalkane in 1 ml.
As a general trend there is increased reaction rate with decreas-
ing acidity of the acidic co-catalyst with no dramatic change in
enantioselectivity. These observations are in line with a recent
report from Gellman et al., on the involvement of proton sources
as co-catalysts.19 Typically, in presence of 4-nitrophenol, the reac-
tion performed six times faster than for the original catalyst (entry
3). Although, phosphoric acid (H3PO4) provided an improved enan-
tioselctivity, it also required a much longer reaction time. This
could be due to the stronger conjugated base, which could assist
in proton transfer in the activated complex. This raises the specu-
lation as to whether the reaction proceeds through a mechanism
involving electrophilic activation of the enone via hydrogen
bonding.
To further evaluate the sensitivity of the reaction to conditions,
we examined the presence of water as an additive at various con-
centrations (see Table 4). As a confirmation, addition of up to
10 mol % (1.0 equiv to catalyst) of water to catalyst 7 did not affect
the reaction dramatically. However, the presence of water at high-
er concentrations resulted in the steady erosion of the enantiose-
lectivity. These results are in contrast to those reported by Ley
et al. who observed no decline in stereoselectivity during the addi-
tion of 2-nitropropane to methyl-4-phenyl-3-buten-2-one cata-
lyzed by tetrazole catalyst 4.14
a
Standard conditions were used: 10 mol % 8, 25 mol % trans-2,5-dimethylpiper-
azine and 1.5 equiv nitroalkane in 1 ml solvent, two days.
to those developed earlier for the nitroalkylation of enones, a range
of solvents for the reaction was investigated (Table 2). Thus, in
each case the desired product was formed with high conversion
and the reaction was clearly enantioselective. These results re-
vealed that hydrogen bonding stabilizing solvents such as DMSO,
EtOH, and MeOH gave low to moderate enantioselectivities, while
the use of tert-amylalcohol, hexane, and DMF resulted in a notice-
able improvement. This observation suggested competing hydro-
gen bonding networks in the transition state. Changing the
solvent to CHCl3 gave a higher enantioselectivity of 87:13, while
maintaining an efficient reaction (Table 2, entry 1). On the other
hand, the use of the non-chlorinated solvents, MeCN, DEE, dioxane,
MTBE, and THF provided conversions over 90% and similar enantio-
selectivities with THF proving to be the optimal reaction solvent.
The low selectivity encountered with protic solvents may be attrib-
uted to their ability to disturb hydrogen-bonds in the transition
state. The fact that this effect is minimized with non-polar protic
solvents suggests that the transition state is highly polar, as pro-
posed by Hanessian et al.,10 and the repulsion between solvent
and the active complex prevents hydrogen bonding. Surprisingly,
hexane, a highly non-polar solvent, only furnished the correspond-
ing product with modest selectivity.
Table 4
Water dependency in a THF systema
Water in THF (%)
Waterb (mol %)
Conversion (%)
er 9 (%)
0
0.5
2.7
5.4
10.8
21.6
0
10
50
100
200
400
90
95
99
94
89
86
88:12
87:13
77:23
59:41
50:50
50:50
2.4. Effect of water and acidic co-catalyst
During our investigation of the Michael addition of 2-nitropro-
pane to cyclohexenone, we noticed an improved reaction rate for
reactions performed with solid catalyst 8. Indeed, a-aminophosph-
onate 7 crystallized upon standing when exposed to air. Further, 1H
and 13C NMR analyses revealed spectroscopic data comparable to
those of the corresponding hydrochloride salt, which is readily
accessible. These observations suggest that hydration of 7 into 8
had occurred upon exposure to moist air for a certain time. Thus,
free amine 7 could be regenerated upon treatment of the crystal-
line compound 8 with NaOH (2 M) and extraction with dichloro-
methane. While catalyst 8 displayed a threefold increase in the
addition reaction rate than the freshly prepared catalyst 7, there
was no change in enantioselectivity.
a
All reagents, solvents, and reaction vessels were dried prior to use. Standard
conditions were used, that is, 10 mol % 7, 25 mol % trans-2,5-dimethylpiperazine,
and 1.5 equiv nitroalkane in 1 ml. The reaction was run for 5 days.
b
With respect to cyclohexenone.
Having established that
a-aminophosphonate 8 is an effective
catalyst for the addition of 2-nitropropane to cyclohexenone, we
then considered the extension of this study to a variety of enones
and nitroalkanes.
The observed improvement in the catalytic activity of
prompted us to investigate the reactivity of a variety of acidic
8
As a first extension of the Michael reaction to other substrates,
the optimized reaction conditions were applied to various

M. Malmgren et al. / Tetrahedron: Asymmetry 19 (2008) 1934–1940
1937
Table 6
nitroalkanes with cyclohexenone. Generally, these reactions per-
The Michael addition of various nitroalkanes to 3-methylcyclohexenonea
formed well although in the presence of only 25 mol % of trans-
2,5-dimethylpiperazine, and provided products in high yields and
good enantioselectivities. However, the results were less satisfac-
tory with nitromethane, while the reaction remained very enantio-
selective. The low yield of the nitromethane adduct can be
attributed to the formation of by-products, presumably from a sec-
ond addition reaction with another cyclohexenone. Higher concen-
trations of trans-2,5-dimethylpiperazine could allow for shorter
reaction times (see Table 5).
O
O
8 (10 mol%)
Base
R1
+
O2N
NO2
1 R2
R2
THF, rt
R
Product Nitroalkane Reaction time
(days)
Conversionb Yield
dr
er
(%)
(%)
22
23
R = R0 = H
R = H,
14
14
61
63
57
54
—
86:14
63:37 88:12
80:20
72:28 91:9
71:29
Table 5
R0 = Me
R = H,
Michael addition of various nitroalkanes to cyclopentenone and cyclohexenonea
24
14
14
46
29
—
R0 = Et
R = R0 = Me
O
25
No reaction
—
—
O
a
8 (10 mol%)
Standard conditions were used, that is, 10 mol % 8, 25 mol % trans-2,5-
R1
Base
dimethylpiperazine, and 1.5 equiv nitroalkane in THF.
NO2
1 R2
+
O2N
b
( )n
Determined by chiral GC.
R2
THF, rt
( )n
R
Michael addition was detected with 2-nitropropane and 3-
methylcyclohexenone.
Product
n
Nitroalkane
Reaction Conversionb Yieldc drb
erb
time (h)
(%)
(%)
15
16
17
0
1
0
R1 = R2 = H
168
149
57
84
99
97
15
18
64
—
N.R.d
90:10
A less reactive acceptor in the Michael addition, 4-phenyl-3-
buten-2-one, displayed lower enantioselectivity than cyclic
substrates. Typically, the reaction of 4-phenyl-3-buten-2-one with
2-nitropropane afforded 98% conversion and 68:32 er over six days
(Table 7). By changing the Michael donor to less congested
nitroalkanes, we obtained good results both with nitroethane and
1-nitropropane. These reactions provided a slightly improved er
R1 = R2 = H
R1 = H, R2 = Me
52:48 84:16
84:16
18
19
20
1
0
1
R1 = H, R2 = Me
R1 = H, R2 = Et
R1 = H, R2 = Et
70
80
70
97
97
96
85
72
80
53:47 88:12
87:13
51:49 87:13
87:13
51:49 89:11
90:10
of 76:24, and gave
1-nitropropane.
a higher 3:2 diastereomeric ratio with
21
9
0
1
R1 = R2 = Me
R1 = R2 = Me
80
70
100
96
68
78
—
86:14
88:12
Table 7
a
Standard conditions were used, that is, 10 mol % 8, 25 mol % trans-2,5-dimethyl-
The Michael addition of different nitroalkanes to 4-phenyl-3-buten-2-onea
piperazine, and 1.5 equiv nitroalkane in THF.
b
R2
Determined by chiral GC.
Isolated yield.
Not resolved on chiral GC.
R1
c
O2N
Ph
8 (10 mol%)
O
O
R1
R2
Base
d
+
O2N
Ph
THF, rt
Higher nitroalkanes provided the Michael products in high yield
and retained the high stereoselectivity at the b-position, however;
virtually no stereocontrol was achieved at the exocyclic
stereocenter. The poor selectivities generally observed at the acidic
Product
Nitroalkane
1 = R2 = H
Reaction
time (days)
Conversionb
(%)
drc
er
26
27
R
6
6
92
95
—
53:47
N.R.d
R1 = H, R2 = Me
R1 = H, R2 = Et
R1 = R2 = Me
76:24
76:24
76:24
N.R.d
c
-position have been attributed to epimerization under the basic
conditions typically required for these reactions. The -amino-
a
28
6
6
97
98
60:40
—
phosphonate 8 was also effective for the Michael addition of
nitroalkanes to cyclopentanone. Similar to the reaction with
cyclohexenone, nitromethane often led to a side reaction at the
expense of the target 1,4-addition product. Unfortunately, the
enantiomers of 3-nitromethylcyclopentanone could not be sepa-
rated on chiral GC. In general, with the exception of nitromethane,
reactions with cyclopentenone as a Michael acceptor provided the
1,4-addition product in moderate to good yield and good enanti-
oselectivity. However, the diastereoselectivity remains a desirable
achievement.
29
68:32
a
Standard conditions were used, that is, 10 mol % 8, 25 mol % trans-2,5-
dimethylpiperazine and 1.5 equiv nitroalkane in THF.
b
Determined by GC and NMR.
Determined by NMR.
Not resolved on chiral GC.
c
d
3. Conclusion
The use of bulkier 3-methylcyclohexenone, a rather uncommon
substrate, for the addition of nitroalkanes was particularly tempt-
ing. The desired enantioselective nitro-addition would ensue, set-
ting up a new quartenary stereogenic center, a more challenging
operation than that for tertiary stereogenic centers (see Table 6).
In contrast to earlier reactions with nitromethane, 3-methylcyc-
lohexenone is free from the drawbacks of side reactions. This is
most likely due to the increased steric congestion of the substrate,
thus preventing the addition of another 3-methylcyclohexenone.
Despite the low reaction rate, good enantioselectivity was obtained
and a well-defined diastereoselectivity, whereby the major diaste-
reomer also shows the best enantioselectivity. Unfortunately, no
In conclusion, we have introduced chiral a-aminophosphonates
as a new class of efficient catalysts for the asymmetric Michael
addition of nitroalkanes to enones. The reaction provides good
results for a range of substrates; the products are isolated in high
yields with good to high enantioselectivities. Optimized reaction
conditions also allow for catalytic loading (25 mol %) of trans-2,5-
dimethylpiperazine as a base, using only 1.5 equiv of the nitroal-
kane. Furthermore, proton sources can be employed as acidic
co-catalysts to ensure high reactivity while keeping a high level
of enantioselectivity, thus alluding to the involvement of general
acid catalysis. Thus, mechanistic studies are underway to develop
more efficient aminophosphonate catalysts.

1938
M. Malmgren et al. / Tetrahedron: Asymmetry 19 (2008) 1934–1940
d = 4.23 (4H, m, P(@O)OCH2), 3.73 (1H, m, PCHN), 3.37 (2H, m,
NCH2), 2.28–1.97 (4H, m, pyrrol-H), 1.37 (6H, m, POCH2CH3).
4. Experimental
4.1. General information
4.6. Diethyl (2R)-tetrahydropyrro-2-ylphosphonate
p-tolulenesulfonate 14
Unless otherwise noted, materials were purchased from com-
mercial suppliers and used without further purification. All sol-
vents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over Na2SO4. Thin
layer chromatography was performed on aluminum plates coated
with 60 F254 silica. Plates were visualized using UV light
(254 nm) and phosphomolybdic acid (10% solution in ethanol).
Flash column chromatography was performed on Kieselgel 60 sil-
ica (230–400 mesh). 1H NMR spectra were recorded on Varian
Unity 400 (400 MHz) spectrometer. Chemical shifts are reported
in ppm from the solvent resonance as the internal standard
(CDCl3: 7.27 ppm). Data are reported as follows: chemical shift,
multiplicity (s = single, d = doublet, t = triplet, m = multiplet), cou-
pling constants (Hz), and integration. 13C NMR spectra were re-
corded on Varian Unity 400 (100 MHz) with complete proton
decoupling (CDCl3: 77.23 ppm). Chiral GC separations were per-
formed using a Varian 3400 with a chiral column (Chirasil Dex-
CB) using nitrogen as the carrier gas. The racemic samples were
prepared by either using racemic proline or DBU as the catalyst.
The major enantiomer was assigned by comparison of racemic
Dry catalyst 19 (28.4 mg, 0.137 mmol) was dissolved in DEE
(0.5 ml), and p-toluenesulfonicacid monohydrate (26 mg, 0.136
mmol) was added and left to evaporate in air. The title compound
was obtained in quantitative yield as a yellow viscous oil. 1H NMR
(400 MHz, CDCl3): d = 9.89 (1H, br s, NHH0), 8.89 (1H, br s, NHH0),
7.75 (2H, d, J = 8 Hz, S(O)2ArH), 7.18 (2H, d, J = 8 Hz, CH3ArH),
4.20 (4H, m, P(@O)OCH2), 3.93 (1H, m, PCHN), 3.51 (2H, m,
NCH2), 2.34 (3H, s, PhCH3), 2.33–2.01 (4H, m, pyrrol-H), 1.32 (6H,
m, POCH2CH3).
4.7. General procedure: nitroalkane Michael addition to enones
Catalyst 8 (0.033 mmol, 10 mol %), trans-2,5-dimethylpipera-
zine (0.0825 mmol, 25 mol %), enone (0.33 mmol), and nitroalkane
(0.5 mmol) were added to a vial together with THF (270 ll). The
mixture was stirred at rt and monitored with chiral GC. Samples
were quenched by adding ethylacetate (2 ml) and NH4Cl(sat)
(1 ml). The aqueous phase was extracted with additional ethylace-
tate (1 ml). The organic phases were combined and dried with
Na2SO4, and the solvent removed under reduced pressure. Column
chromatography on silica gel afforded pure product.
Michael products with those reported in the literature using
proline.
L-
4.2. Diethyl (2R)-tetrahydropyrro-2-ylphosphonate 4-
nitrophenolate 10
4.8. (S)-3-(Nitromethyl)cyclopentanone 1510b
Dry catalyst 7 (7.5 mg, 0.036 mmol) was dissolved in THF
(0.5 ml) and p-nitrophenol (5 mg, 0.036 mmol) was added and left
to evaporate in air. The title compound was obtained in quantita-
tive yield as a yellow-green viscous oil. 1H NMR (400 MHz, CDCl3):
d = 8.14 (2H, d, J = 8 Hz, NO2ArH), 6.94 (2H, d, J = 8 Hz, OArH), 4.20
(4H, m, P(@O)OCH2), 3.52 (1H, m, PCHN), 3.17 (2H, m, NCH2), 2.38–
1.95 (4H, m, pyrrol-H), 1.36 (6H, t, J = 6.8 Hz, POCH2CH3).
The reaction mixture was quenched after 168 h. Purification
using column chromatography (EtOAc–heptane 1:2) gave the title
compound as a colorless oil (7.0 mg, 0.049 mmol, 15%). 1H NMR
(400 MHz, CDCl3): d = 4.48 (2H, d, J = 7.2 Hz, NO2CH2), 3.06–2.98
(1H, m, CHCH2NO2), 2.58–2.52 (1H, m, C(@O)CHH0CHR), 2.46–
2.23 (3H, m, C(@O)CHH0CHR, C(@O)CH2CH2), 2.06–1.98 (1H, m),
1.76–1.58 (2H, m). Chiral GC: Chirasil Dex-CB could not resolve
enantiomers.
4.3. Diethyl (2R)-tetrahydropyrro-2-ylphosphonate
hydrochloride 11
4.9. (S)-3-(Nitromethyl)cyclohexanone 1614a
Dry catalyst 7 (29.6 mg, 0.143 mmol) was dissolved in EtOH/HCl
(0.5 ml, ꢀ1 M) and left to evaporate in air. A yellow-brown viscous
oil was obtained in quantitative yield. 1H NMR (400 MHz, CDCl3):
d = 5.03 (2H, br s, N+H2), 4.28 (4H, m, P(@O)OCH2), 3.90 (1H, m,
PCHN), 3.50 (2H, m, NCH2), 2.32–2.07 (4H, pyrrol-H), 1.40 (6H, m,
POCH2CH3).
The reaction mixture was quenched after 149 h. Purification
using column chromatography (EtOAc–heptane 1:3) gave the title
compound as a colorless oil (9.4 mg, 0.0599 mmol, 18%). 1H NMR
(400 MHz, CDCl3): d = 4.36 (2H, m, CH2NO2), 2.66 (1H, m,
CHCH2NO2), 2.48 (1H, m, C(@O)CHH0CH), 2.42 (1H, m,
C(@O)CHH0CH2) 2.34–2.26 (1H, m, C(@O)CH0HCH2), 2.20–2.14
(1H, m, C(@O)CH0HCH), 2.16–2.10 (1H, m, C(@O)CH2CHH0), 2.01–
2.97 (1H, m, CHRCHH0), 1.78–1.69 (1H, m, C(@O)CH2CHH0), 1.57–
1.47 (1H, m, CHRCHH0). Chiral GC: Chirasil Dex-CB, 125 °C,
56.9 min (major), 57.9 min (minor) gave 90:10 er.
4.4. Diethyl (2R)-tetrahydropyrro-2-ylphosphonate acetate 12
Dry catalyst 19 (21.4 mg, 0.103 mmol) was dissolved in AcOH
(0.5 ml) and left to evaporate in air. The title compound was ob-
tained in quantitative yield as a yellow viscous oil. 1H NMR
(400 MHz, CDCl3): d = 8.02 (2H, br s, NH2), 4.19 (4H, m,
P(@O)OCH2), 3.58 (1H, m, PCHN), 3.15 (2H, m, NCH2), 2.18–1.87
(4H, m, pyrrol-H), 2.08 (3H, s, CH3C(@O)), 1.35 (6H, t, J = 6.8 Hz,
POCH2CH3).
4.10. (10R,3S)-3-(Nitroethyl)cyclopentanone and (10S,3S)-3-
(nitroethyl)cyclopentanone 1710b
The reaction mixture was quenched after 57 h. Purification
using column chromatography (EtOAc–heptane 1:2) gave the title
compound as a colorless oil (33.2 mg, 0.210 mmol, 64%). 1H NMR
(400 MHz, CDCl3): d = 4.52 (1H, m, CHNO2), 2.78–2.68 (1H, m,
NO2CHCH) 2.48–2.37 (2H, m, C(@O)CH2CH2), 2.31–2.15 (2H, m,
C(@O)CH2CHR), 2.13–2.04 (1Hmaj, m, C(@O)CH2HH0), 1.98–1.91
(1Hmin, m, C(@O)CH2HH0), 1.77–1.64 (1H, m, C(@O)CH2HH0), 1.63
4.5. Diethyl (2R)-tetrahydropyrro-2-ylphosphonate
hydrophosphate 13
Dry catalyst 19 (10.46 mg, 0.051 mmol) was dissolved in THF
(0.5 ml), and phosphonicacid (5 mg, 0.051 mmol) was added and
left to evaporate in air. The title compound was obtained in quan-
titative yield as a clear viscous oil. 1H NMR (400 MHz, CDCl3):
(3Hmin, d, J = 6.4 Hz, NO2CHCH3), 1.60 (3Hmaj, d, J = 6.8 Hz,
NO2CHCH3). Chiral GC: Chirasil Dex-CB, 120 °C, major
diastereoisomer: 33.7 min (major), 34.9 min (minor); minor

M. Malmgren et al. / Tetrahedron: Asymmetry 19 (2008) 1934–1940
1939
diastereoisomer: 36.8 min (major), 37.5 min (minor) gave 52:48 dr
and 84:16/84:16 er.
Chirasil Dex-CB, 130 °C, 35.5 min (major), 36.7 min (minor) gave
88:12 er.
4.11. (10R,3R)-3-(10-Nitroethyl)cyclohexanone and (10S,3R)-3-
4.16. (S)-3-Methyl-3-(nitromethyl)cyclohexanone 2214a
(10-nitroethyl)cyclohexanone 1814a
The reaction mixture was quenched after 14 days. Purification
using column chromatography (EtOAc–heptane 1:6) gave the title
compound as a colorless oil (27.7 mg, 0.187 mmol, 57%). 1H NMR
(400 MHz, CDCl3): d = 4.30 (2H, dd, J = 20.0, 10.8 Hz, CH2NO2),
2.45–2.05 (4H, m, CH2C(@O)CH2), 2.06–1.71 (4H, m,
C(@O)CH2CH2CH2), 1.13 (3H, s, CH3). Chiral GC: Chirasil Dex-CB,
125 °C, 32.8 min (major), 34.3 min (minor) gave 86:14 er.
The reaction mixture was quenched after 70 h. Purification using
column chromatography (EtOAc–heptane 1:3) gave the title com-
pound as a colorless oil (47.7 mg, 0.279 mmol, 84.5%). 1H NMR
(400 MHz, CDCl3): d = 4.51 (1H, m, CHNO2), 2.49–2.42 (2H, m,
C(@O)CH2CH), 2.37–2.23 (2H, m, C(@O)CH2CH2), 2.18–2.09 (2H, m,
C(@O)CH2CHH0 CH2CHR), 1.97–1.87 (1H, m, CHCHH0), 1.72–1.66
(1H, m, C(@O)CH2CHH0), 1.62–1.42 (5H, m, C(NO2)HCH3, CH2CH2CH).
Chiral GC: Chirasil Dex-CB, 120 °C, major diastereoisomer: 40.9 min
(minor), 41.4 min (major); minor diastereoisomer: 46.2 min (major),
47.8 min (minor) gave 53:47 dr and 88:12/87:13 er.
4.17. (10R,3S)-3-Methyl-3-(nitroethyl)cyclohexanone and
(10S,3S)-3-methyl-3-(nitroethyl)cyclohexanone 23
The reaction mixture was quenched after 14 days. Purification
using column chromatography (EtOAc–heptane 1:8) gave the title
compound as a colorless oil (33.4 mg, 0.179 mmol, 54%). 1H NMR
(400 MHz, CDCl3): d = 4.52 (1H, q, J = 7.2 Hz, CHNO2), 2.54–1.98
(5H, m, CH2C(@O)CH2, C(@O)CH2CHH0), 1.89–1.63 (3H, m,
4.12. (10R,3S)-3-(10-Nitropropyl)cyclopentanone and (10S,3S)-3-
(10-nitropropyl)cyclopentanone 19
The reaction mixture was quenched after 80 h. Purification using
column chromatography (EtOAc–heptane 1:3) gave the title com-
pound as a colorless oil (40.7 mg, 0.236 mmol, 72%). 1H NMR
(400 MHz, CDCl3): d = 4.34 (1H, dt, J = 9.6, 3.2 Hz, NO2CH), 2.73
(1H, m, NO2CHCH), 2.49–2.35 (2H, m, C(@O)CH2CH2), 2.30–2.20
(1H, C(@O)CHH0CHR), 2.18–1.92 (3H, m, C(@O)CHH0CHR,
C(@O)CH2CHH0), 1.85–1.59 (3H, m, C(@O)CH2CHH0, NO2CHCH2),
1.01 (3Hmin, t, J = 7.4 Hz, CH2CH3), 1.00 (3Hmaj, t, J = 7.4 Hz, CH2CH3).
Chiral GC: Chirasil Dex-CB gave 49:51 dr and 87:13/87:13 er.
C(@O)CH2CHH0, CH2CH2CHR), 1.52 (3Hmin
,
d, J = 6.4 Hz,
CHNO2CH3), 1.51 (3Hmaj d, J = 6.8 Hz, CHNO2CH3), 1.02 (3Hmaj, s,
CRCH3), 1.00 (3Hmin, s, CRCH3). Chiral GC: Chirasil Dex-CB, 125 °C,
major diastereoisomer: 33.8 min (major), 35.4 min (minor); minor
diastereoisomer: 38.2 min (major), 41.6 min (minor) gave 63:37 dr
and 88:12/80:20 er.
4.18. (10R,3S)-3-Methyl-3-(nitropropyl)cyclohexanone and
(10S,3S)-3-methyl-3-(nitropropyl)cyclohexanone 24
4.13. (10R,3S)-3-(10-Nitropropyl)cyclohexanone and (10S,3S)-3-
(10-nitropropyl)cyclohexanone 2010b
The reaction mixture was quenched after 14 days. Purification
using column chromatography (EtOAc–heptane 1:10) gave the title
compound as a colorless oil (19.1 mg, 0.097 mmol, 29%). 1H NMR
(400 MHz, CDCl3): d = 4.27 (1H, dt, J = 9.2, 1.8, CHNO2), 2.58–2.12
(4H, m, CH2C(@O)CH2), 2.11–1.98 (2H, m, C(@O)CH2CHH0,
CHNO2CHH0), 1.88–1.73 (3H, m, C(@O)CH2CHH0, CHNO2CHH0,
CH2CHH0C(CH3)R), 1.72–1.57 (1H, m, CH2CHH0C(CH3)R), 1.05
(3Hmaj, s, CRCH3), 1.01 (3Hmin, s, CRCH3), 0.96 (3H, t, J = 7.0,
CH2CH3). 13C NMR (100 MHz, CDCl3): d = 209.52, 99.69 (min),
98.48 (maj), 50.50 (maj), 48.89 (min), 41.98 (maj), 41.43 (min),
40.83, 33.19 (min), 33.04 (maj), 21.54, 21.34, 20.73, 11.18. Chiral
GC: Chirasil Dex-CB, 130 °C, major diastereoisomer: 30.1 min (ma-
jor), 32.2 min (minor); minor diastereoisomer: 35.3 min (major),
37.3 min (minor) gave 72:28 dr and 91:9/71:29 er.
The reaction mixture was quenched after 70 h. Purification
using column chromatography (EtOAc–heptane 1:3) gave the title
compound as a colorless oil (48.6 mg, 0.262 mmol, 79.4%). 1H NMR
(400 MHz, CDCl3): d = 4.38–4.27 (1H, m, CHNO2), 2.52–2.40 (2H, m,
C(@O)CH2CH), 2.33–2.23 (3H, m, C(@O)CH2CH2, C(@O)CH2CHH0),
2.16–2.07 (1H, m, CHH0CH3), 2.05–1.93 (1H, m, C(@O)CH2CHR0),
1.88–1.78 (2H, m, CH2CH2CHR), 1.69–1.42 (2H, m, CHH0CH3,
C(@O)CH2CHH0), 0.99–0.95 (3H, m, CH3). Chiral GC: Chirasil Dex-
CB, 125 °C, major diastereoisomer: 38.2 min (major), 38.9 min
(minor); minor diastereoisomer: 42.5 min (major), 43.3 min (min-
or) gave 51:49 dr and 89:11/90:10 er.
4.14. (S)-3-(2-Nitropropane-2-yl)cyclopentanone 2114a
4.19. (4S)-5-Nitro-4-phenylpenta-2-one 2614a
The reaction mixture was quenched after 80 h. Purification
using column chromatography (EtOAc–heptane 1:3) gave the title
compound as a colorless oil (38.3 mg, 0.223 mmol, 68%). 1H NMR
(400 MHz, CDCl3): d = 2.86 (1H, m, CHC(CH3)2NO2), 2.45–2.20
(3H, m, CH2C(@O)CHH0), 2.14–2.03 (2H, m, C(@O)CHH0,
C(@O)CH2CHH0), 1.74–1.60 (1H, m, C(@O)CH2CHH0), 1.63 (3H, s,
CH3), 1.62 (3H, s, CH3). Chiral GC: Chirasil Dex-CB gave 86:14 er.
The reaction mixture was quenched after six days. NMR analy-
sis showed the title compound in 91% compared to other species.
1H NMR (400 MHz, CDCl3): d = 7.40–7.21 (5H, m, ArH), 4.70 (1H,
dd, NO2CHH0), 4.60 (1H, dd, NO2CHH0), 4.01 (1H, m, PhCH), 2.93
(2H, dd, J = 6.8 Hz, C(@O)CH2CHPhR), 2.13 (2H, s, CH3C(@O)). Chiral
GC: Chirasil Dex-CB could not resolve enantiomers.
4.20. (4S,5R)-5-Nitro-4-phenylhexan-2-one and (4S,5S)-5-nitro-
4.15. (S)-3-(2-Nitropropane-2-yl)cyclohexanone 914a
4-phenylhexan-2-one 2714a
The reaction mixture was quenched after 70 h. Purification
using column chromatography (EtOAc–heptane 1:3) gave the title
compound as white crystals (47.6 mg, 0.256 mmol, 78%). 1H NMR
(400 MHz, CDCl3): d = 2.45–2.36 (3H, m, CHCNO2, C(@O)CHH0CH2,
C(@O)CHH0CH), 2.26–2.21 (1H, m, C(@O)CHH0CH2), 2.16–2.09
(2H, m, C(@O)CHH0CH, C(@O)CH2CHH0), 1.82–1.79 (1H, m,
CHRCHH0CH2), 1.64 (1H, m, C(@O)CH2CHH0), 1.58 (3H, s, CH3),
1.57 (3H, s, CH03), 1.47–1.40 (1H, m, CHRCHH0CH2). Chiral GC:
The reaction mixture was quenched after six days. NMR analy-
sis showed the title compound in 92% compared to other species
with 53:47 dr. 1H NMR (400 MHz, CDCl3): d = 7.35–7.13 (5H, m,
ArH), 4.89 (1Hmin, m, NO2CH), 4.76 (1Hmaj, m, NO2CH), 3.72 (1H,
m, PhCH), 3.09–2.72 (2H, m, C(@O)CH2CHPhR), 2.13 (3Hmin, s,
CH3C(@O)), 2.02 (3Hmaj, s, CH3C(@O)), 1.49 (3Hmin, d, J = 6.8 Hz,
NO2CHCH3), 1.33 (3Hmaj, d, J = 6.4 Hz, NO2CHCH3). Chiral GC:
Chirasil Dex-CB, 130 °C, major diastereoisomer: 28.9 min (major),

1940
M. Malmgren et al. / Tetrahedron: Asymmetry 19 (2008) 1934–1940
Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis; Ojima, I., Ed., 2nd ed.;
Wiley: New York, 2000; p 569; (e) Tomioka, K.; Nagaoka, Y. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; Vol. 3,. Chapter 31.1.
29.6 min (minor); minor diastereoisomer: 32.7 min (major), 33.6
min (minor) gave 76:24/76:24 er.
2. Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105,
933.
3. Bakò, T.; Bakò, P.; Keglevich, G.; Báthori, N.; Czugler, M.; Tatai, J.; Novák, T.;
Parlagh, G.; Töke, L. Tetrahedron: Asymmetry 2003, 14, 1917; Bakò, T.; Bakò, P.;
Szöllösy, A.; Czugler, M.; Keglevich, G.; Töke, L. Tetrahedron: Asymmetry 2002,
13, 203.
4. Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki, M. Tetrahedron
Lett. 1998, 39, 7557.
5. Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc.
2005, 127, 1313.
6. (a) Reviews on organocatalysis, see: Enantioselective Organocatalysis; Dalko, P.
I., Ed.; Wiley-VCH: Weinheim, 2007; (b) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005; (c) Gaunt, M. J.; Johnsson, C. C.
C.; McNally, A.; Vo, N. T. Drug Discov. Today 2007, 12, 8; (d) List, B. Chem.
Commun. 2006, 819; (e) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006,
2001; (f) Hayashi, Y. J. Synth. Org. Chem. Jpn. 2005, 63, 464; (g) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (h) List, B. Tetrahedron 2002,
58, 5573; (i) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007,
107, 5471.
7. (a) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257; (b) Colonna, S.; Hiemstra,
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Wynberg, H. J. Chem. Soc., Perkin Trans. 1 1981, 547.
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35, 8233; (b) Yamaguchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama, M.
Tetrahedron 1997, 53, 11 223.
4.21. (4S,5R)-5-Nitro-4-phenylheptan-2-one and (4S,5S)-5-
nitro-4-phenylheptan-2-one 28
The reaction mixture was quenched after six days. NMR analy-
sis showed the title compound in 94% compared to other species
with 60:40 dr. 1H NMR (400 MHz, CDCl3): d = 7.35–7.13 (5H, m,
ArH), 4.70 (1Hmin, m, NO2CH), 4.58 (1Hmaj, m, NO2CH), 3.77–3.67
(1H, m, PhCH), 3.06–2.65 (2H, m, C(@O)CH2CHPhR), 2.11 (3Hmin
,
s, CH3C(@O)), 1.99 (3Hmaj s, CH3C(@O)), 1.94–1.75 (2H, m,
,
NO2CHCH2), 0.96 (3Hmin, t, J = 7.2 Hz, CH2CH3), 0.84 (3Hmin, t,
J = 7.2 Hz, CH2CH3). Chiral GC: Chirasil Dex-CB, 125 °C, major dia-
stereoisomer: 41.0 min (minor), 41.6 min (major) gave 76:24 er
and could not resolve the second diastereomer at 49.8 min.
4.22. (S)-5-Methyl-5-nitro-4-phenylhexan-2-one 2914a
The reaction mixture was quenched after six days. NMR analy-
sis showed the title compound in 95% compared to other species.
1H NMR (400 MHz, CDCl3): d = 7.33–7.19 (5H, m, ArH), 3.95 (1H,
dd, J = 3.2, 10.8 Hz, PhCH), 3.09 (1H, dd, J = 11.2, 17.2 Hz,
C(@O)CHH0), 2.72 (1H, dd, J = 3.6, 17.2 Hz, C(@O)CHH0), 2.04 (3H,
s, C(@O)CH3), 1.56 (3H, s, C(NO2)CH3), 1.49 (3H, s, C(NO2)CH3). Chi-
ral GC: Chirasil Dex-CB, 140 °C, 22.2 min (major), 22.7 min (minor)
gave 68:32 er.
10. (a) Hanessian, S.; Govindan, S.; Warrier, J. S. Chirality 2005, 17, 540; (b)
Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975.
11. Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
8331.
12. Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897.
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Tetrahedron: Asymmetry 2006, 17, 989; (b) Tsogoeva, S. B.; Jagtap, S. B.;
Ardemasova, Z. A.; Kalikhevich, V. N. Eur. J. Org. Chem. 2004,
4014.
Acknowledgments
14. (a) Mitchell, C. E. T.; Brenner, S. E.; Garc´ıa-Fortanet, J.; Ley, S. V. Org. Biomol.
Chem. 2006, 4, 2039; (b) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem.
Commun. 2005, 5346.
15. (a) Ooi, T.; Doda, K.; Takeda, S.; Maruoka, K. Tetrahedron Lett. 2006, 47, 145; (b)
Ooi, T.; Motimoto, K.; Doda, K.; Maruoka, K. Chem. Lett. 2004, 33, 824; (c) Ooi,
T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 9022.
16. Hojabri, L.; Hartikka, A.; Moghaddam, F. M.; Arvidsson, P. I. Adv. Synth. Catal.
2007, 349, 740.
This work was supported by the Swedish Research Council (Vet-
eskapsrådet) and The Royal Society of Arts and Sciences (KVVS).
AstraZeneca (Award for Excellence in Undergraduate Research in
Organic Chemistry 2008 to M.M.) is gratefully acknowledged.
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