Chiral thiourea-catalyzed asymmetric michael addition of β-oxo phosphonate to nitro olefins: Convenient synthesis of optically active β-oxo phosphonates

Article abstract of DOI:10.1002/ejoc.201100029

β-Oxo phosphonates have been proven to be alternative Michael donors in Michael addition reactions to nitro olefins in the presence of cinchonine-based bifunctional thiourea, affording a direct and atom-economic approach to the efficient construction of synthetically and biologically valuable chiral acyclic α-substituted β-oxo phosphonates with high levels of enantioselectivity (up to 98 % ee). A direct and atom-economic approach to the preparation of synthetically and biologically valuable optically active acyclic α-substituted β-oxo phosphonates with high levels of enantioselectivity (up to 98 % ee)has been developed that involves chiral thiourea-catalyzed asymmetric Michael addition of β-oxo phosphonates to nitro olefins. Copyright

Full text of DOI:10.1002/ejoc.201100029

FULL PAPER
DOI: 10.1002/ejoc.201100029
Chiral Thiourea-Catalyzed Asymmetric Michael Addition of β-Oxo
Phosphonate to Nitro Olefins: Convenient Synthesis of Optically Active β-Oxo
Phosphonates
Kuang Hu,[a] Tao Liu,[a] A. D. Lu,[a] Yunfeng Liu,[a] Youming Wang,*[a] Guiping Wu,[a]
Zhenghong Zhou,*[a] and Chuchi Tang[a]
Keywords: Enantioselectivity / Oxo phosphonates / Michael addition / Organocatalysis / Asymmetric catalysis
β-Oxo phosphonates have been proven to be alternative
Michael donors in Michael addition reactions to nitro olefins
in the presence of cinchonine-based bifunctional thiourea,
affording a direct and atom-economic approach to the ef-
ficient construction of synthetically and biologically valuable
chiral acyclic α-substituted β-oxo phosphonates with high
levels of enantioselectivity (up to 98% ee).
β-oxo phosphonates have been reported. By using (S)-1-
phenylethylamine as a chiral auxiliary, Delarue-Cochin et
al. realized the diastereoselective Michael addition of chiral
β-enamino phosphonate to various activated alkenes, which
afforded α,α-disubstituted β-oxo phosphonates after re-
moval of the chiral auxiliary.[9] Recently, Jørgensen and co-
workers developed an alternative approach to the synthesis
of enantiomerically enriched β-oxo phosphonates by a chi-
ral diarylprolinol ether organocatalyzed domino Michael–
Knoevenagel reaction of ethyl 4-(diethoxyphosphoryl)-3-
oxobutanoate and α,β-unsaturated aldehydes.[10] Therefore,
the development of a new convenient and atom-economic
approach to optically active α-substituted β-oxo phos-
phonates is highly desirable. Herein we report the first or-
ganocatalyzed asymmetric Michael addition of simple β-
oxo phosphonates to nitro olefins, which afforded valuable
α-substituted β-oxo phosphonates in satisfactory yields
with good to excellent enantioselectivities.
Introduction
Michael addition is one of the most fundamental
carbon–carbon bond-forming reactions. Ever since their
discovery, Michael addition reactions have been very popu-
lar among organic chemists.[1] When nitro olefins are used
as the Michael acceptor, the reaction provides rapid access
to synthetically valuable chiral nitroalkanes. Because of the
multiple reactivity of the nitro functionality, the resulting
adducts can be readily converted into versatile building
blocks for the synthesis of important nitrogen-containing
bioactive agrochemical and pharmaceutical compounds.[2]
As a result, considerable effort has been devoted to the de-
velopment of catalytic enantioselective versions of the pro-
cess. In particular, intensive research aimed at achieving
asymmetric Michael addition to nitro olefins by employing
environmentally friendly organocatalysts has been carried
out in recent years.[3] In these efforts, the Michael donors
used were mainly limited to aldehydes,[4] ketones,[5] and 1,3-
dicarbonyl compounds,[6] such as malonates, 1,3-diketones,
and β-oxo esters. In contrast, until now, organocatalytic
conjugate addition reactions using β-oxo phosphonates as
Michael donors, which represent a direct approach to the
efficient construction of chiral acyclic α-substituted β-oxo
phosphonates, have rarely been studied. It is well known
that β-oxo phosphonates are of great interest not only as
precursors of β-amino and β-hydroxy phosphonates[7] but
also as molecules of biological importance.[8] However, only
two examples of an asymmetric synthesis of α-substituted
Results and Discussion
Similarly to 1,3-dicarbonyl compounds, the hydrogen
atoms situated on the carbon atom between the carbonyl
and phosphoryl groups in simple β-oxo phosphonates are
unusually acidic and can be readily removed by base to
form a nucleophilic enolate anion. We anticipated that bi-
functional thioureas[11] should be particularly well suited as
catalysts to the challenging Michael addition of simple β-
oxo phosphonates to nitro olefins by simultaneous acti-
vation of the β-oxo phosphonate and nitro olefin through
hydrogen-bonding interactions, because their general cata-
lytic activity has been confirmed in numerous Michael ad-
ditions of 1,3-dicarbonyl compounds to nitro olefins.[6]
Thus, bifunctional amine–thioureas 1–5 with different chi-
ral backbones were chosen as potential catalysts (Figure 1).
[a] State Key Laboratory of Elemento-Organic Chemistry, Institute
of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
Fax: +86-22-23508939
E-mail: z.h.zhou@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100029.
Eur. J. Org. Chem. 2011, 3507–3513
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3507

K. Hu, T. Liu, A. D. Lu, Y. Liu, Y. Wang, G. Wu, Z. Zhou, C. Tang
FULL PAPER
Their catalytic activity was evaluated in the reaction of β- much higher chiral induction ability than both primary and
nitrostyrene with diethyl (2-oxo-2-phenylethyl)phosphonate secondary amine–thiourea catalysts (Table 1, Entries 2, 3,
in the presence of 20 mol-% catalyst in toluene at 20 °C, 6–11 vs. Entries 1, 4, 5). In terms of enantioselectivity,
and the results are collected in Table 1.
(1R,2R)-cyclohexane-1,2-diamine-derived thiourea 1c, cin-
chonidine-derived thiourea 4, and cinchonine-based thio-
urea 5a gave the best results (Table 1, Entries 3, 7, and 8;
67, 65, and 68% ee for the major diastereomer, respec-
tively), with catalyst 5a affording adduct 6a in a shorter
time. (1R,2R)-Cyclohexane-1,2-diamine-derived thiourea 1b
and quinine-based thiourea 3 were less effective (Table 1,
Entries 2 and 6; 55 and 48% ee, respectively). Attempts to
further improve the enantioselectivity of the reaction by
changing the electronic characteristics of the N-substituent
of catalyst 5a failed (Table 1, Entry 8 vs. Entries 9–11).
Thus, we chose thiourea 5a as the catalyst for optimization
of the reaction conditions, and the results are listed in
Table 2.
Table 2. Optimization of the reaction conditions for the β-oxo
phosphonate addition to β-nitrostyrene.[a]
Figure 1. Different amine–thiourea organocatalysts.
Entry Solvent
Time [d]
Yield [%][b]
dr[c]
ee [%][d,e]
Table 1. Catalyst evaluation in the β-oxo phosphonate addition to
β-nitrostyrene.[a]
1
2
3
4
5
6
7
8
9
EtOH
MeCN
EtOAc
THF
CHCl3
PhCH3
THF[f]
THF[g]
THF[h]
2.5
3
4
2.5
3
4.5
4
82
83
81
87
84
86
82
86
84
3.3:1
1.8:1
1.7:1
1.6:1
1.6:1
1.6:1
1.6:1
2.2:1
1.5:1
–14 (64)
73 (72)
74 (73)
73 (71)
72 (71)
68 (69)
73 (74)
62 (55)
72 (70)
2
3.5
Entry Catalyst
Time [d]
Yield [%][b]
dr[c]
ee [%][d,e]
[a] Reaction conditions: Nitro olefin (0.2 mmol), β-oxo phos-
phonate (0.4 mmol), solvent (0.6 mL) at 20 °C. [b] Isolated yield.
[c] Determined by 1H and/or 31P NMR spectroscopy. [d] Deter-
mined by chiral HPLC analysis. [e] Data in parentheses are the ee
values of the minor diastereomer. [f] The reaction was carried out
at 10 °C. [g] The reaction was carried out at 30 °C. [h] 15 mol-% of
5a was used.
1
2
3
4
5
6
7
8
9
1a
1b
1c
2a
2b
3
5
81
85
83
83
82
83
85
86
83
80
82
1.1:1
1.2:1
1.2:1
1.8:1
2.5:1
1.5:1
1.6:1
1.2:1
1.6;1
1.3:1
1.4:1
19 (21)
55 (78)
67 (72)
3 (3)
11 (21)
48 (85)
65 (64)
68 (69)
60 (60)
36 (41)
57 (58)
4.5
5.5
4.5
5.5
4.5
4.5
4.5
5
4
5a
5b
5c
5d
A survey of solvents revealed that all the reactions pro-
ceeded smoothly to provide the desired adduct with satis-
factory results. With the exception of ethanol, in which the
product 6a was obtained with a much lower ee and reversed
stereochemistry (Table 2, Entry 1), comparable enantio-
selectivities were observed for the major diastereomer in all
the solvents tested (Table 2, Entries 2–6). With respect to
both enantioselectivity and reaction time, THF is the opti-
10
11
5
5
[a] Reaction conditions: Nitro olefin (0.2 mmol), β-oxo phos-
phonate (0.4 mmol), toluene (0.6 mL). [b] Isolated yield. [c] Deter-
mined by 1H and/or 31P NMR spectroscopy. [d] Determined by
chiral HPLC analysis. [e] Data in parentheses are the ee values of
the minor diastereomer.
As shown in Table 1, all of the thioureas tested exhibited mal reaction solvent. Moreover, the reaction temperature
good catalytic activity in the model reaction. The corre- was found to have a significant influence on the enantio-
sponding Michael addition product, diethyl (4-nitro-1-oxo- selectivity of this reaction. Although the same ee was at-
1,3-diphenylbut-2-yl)phosphonate (6a), was obtained in tained for the major diastereomer when lowering the reac-
good chemical yield (80–86%) in an acceptable reaction tion temperature to 10 °C, the reaction was much slower
time. However, the type of thiourea catalyst used had an (Table 2, Entry 4 vs. Entry 7), increasing the reaction tem-
important influence on the enantioselectivity of the reac- perature to 30 °C resulted in an obvious erosion of the
tion. In general, tertiary amine–thioureas demonstrated enantioselectivity of the reaction (Table 2, Entry 8). In ad-
3508
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3507–3513

Synthesis of Optically Active β-Oxo Phosphonates
dition, the use of smaller amounts of thiourea 5a (15 mol- (Table 3, Entries 8 and 9). Further investigation revealed
%) led to a marked decrease in the reaction rate (Table 1, that the substrate scope is limited to aromatic nitro olefins;
Entry 4 vs. Entry 9).
no reaction occurred even after a prolonged reaction time
Encouraged by these results, we next probed the scope when the aliphatic nitro olefin (E)-1-nitrobut-1-ene was em-
of the reaction with a variety of nitro olefins and different ployed (Table 3, Entry 11).
β-oxo phosphonates under the optimal reaction conditions
To determine the stereochemistry of the reaction, the two
(20 mol-% of thiourea 5a as the catalyst in THF at 20 °C). diastereomers of the conjugate addition product 6a were
The results are summarized in Table 3.
separated by chiral preparative HPLC. The absolute config-
uration of the major diastereomer of product 6a was un-
equivocally established to be (R,R) by X-ray diffraction
(Figure 2).[12] The remaining relative and absolute configu-
rations were assumed by analogy.
Table 3. Substrate scope of 5a-catalyzed asymmetric Michael ad-
dition of β-oxo phosphonates to nitro olefins.[a]
Entry
R, Ar
Time [d] Yield [%][b]
dr[c] ee [%][d,e]
1
2
3
4
5
6
7
8
9
Et, Ph (a)
Me, Ph (b)
2.5
4.5
2.5
3
2.5
3
2.5
3
4
87
85
86
85
86
83
85
84
81
1.5:1
1.6:1
1.1:1
1.7:1
1.3:1
1.7:1
1.3:1
1.6:1
1.3:1
1:1
73 (70)
37 (81)
86 (87)
74 (72)
86 (86)
68 (68)
61 (61)
92 (92)
98 (67)
50 (94)
–
Et, 2-ClC6H4 (c)
Et, 4-ClC6H4 (d)
Et, 2-BrC6H4 (e)
Et, 4-BrC6H4(f)
Et, 3-F3CC6H4 (g)
Et, 2-MeOC6H4 (h)
Et, 1-naphthyl (i)
Et, 2-furyl (j)
10
11
4
7
84
Et, Et (k)
n.r.[f]
–
[a] Reaction conditions: Nitro olefin (0.2 mmol), β-oxo phos-
phonate (0.4 mmol), THF (0.6 mL). [b] Isolated yield of the two
1
inseparable diastereomers. [c] Determined by H and/or 31P NMR
Figure 2. X-ray crystal structure of the major diastereomer of com-
spectroscopy. [d] Determined by chiral HPLC analysis. [e] Data in
parentheses are the ee values of the minor diastereomer. [f] No
reaction occurred.
pound 6a. Most of the hydrogen atoms have been omitted for clar-
ity.
On the basis of the experimental results of the described
reactions, we propose that the reaction proceeds by dual
activation.[13] As shown in the possible transition state for
this reaction in Figure 3, the tertiary amine moiety in 5a
functions as a Lewis base to deprotonate the β-oxo phos-
phonate to form a nucleophilic enolate anion. At the same
time, the nitro olefin is activated by two hydrogen-bonding
interactions between the thiourea subunit and the nitro
group. Nucleophilic attack of the enolate anion at the Re
face of the nitro olefin then results in the formation of the
desired Michael addition product.
As illustrated in Table 3, the ester moieties in the β-oxo
phosphonate seems to have a significant influence on the
reaction. The replacement of the diethyl ester with the di-
methyl ester resulted in a sharp erosion of stereocontrol
(Table 3, Entry 1 vs. Entry 2). More surprising, the bulky
diisopropyl ester was completely inactive in this transfor-
mation and failed to give the desired conjugate addition
product. Moreover, the reaction has broad applicability
with respect to nitro olefins. Not only phenyl, but also elec-
tron-rich and -poor aryl groups and heteroaromatic substit-
uents can be present in the nitro olefin. Note that the posi-
tion of the substituent on the benzene ring has a significant
influence on the stereochemical outcome of the reaction.
In general, the enantioselectivities of the ortho-substituted
substrates are better than those of the corresponding para-
substituted ones (Table 3, Entries 3, 5 vs. Entries 4, 6). This
indicates that steric effects are a key factor in the stereocon-
trol of the reaction, and a sterically more demanding sub-
strate gives higher ee values. To confirm these hypotheses,
the more bulky o-methoxy-substituted β-nitrostyrene and 1-
naphthyl-substituted nitro olefin were examined. As antici-
pated, with an increase in steric hindrance, the enantio-
selectivity of the major diastereomer increased markedly to
Figure 3. Proposed dual activation in the Michael addition reac-
afford adducts 6h and 6i with 92 and 98% ee, respectively tion.
Eur. J. Org. Chem. 2011, 3507–3513
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3509

K. Hu, T. Liu, A. D. Lu, Y. Liu, Y. Wang, G. Wu, Z. Zhou, C. Tang
FULL PAPER
(dd, J = 2.8 and 13.2 Hz, 1 H), 7.16 (br. s, 5 H, aromatic), 7.32 (t,
J = 7.6 Hz, 2 H, aromatic), 7.46 (t, J = 7.2 Hz, 1 H, aromatic),
7.71 (d, J = 7.6 Hz, 2 H, aromatic) ppm. 31P NMR (161.7 MHz,
CDCl3): diastereomeric mixture: δ = 19.20 (minor isomer), 19.32
(major isomer) ppm; (R,R) diastereomer: δ = 19.32 ppm; (R,S) dia-
stereomer: δ = 19.20 ppm. 13C NMR (100.6 MHz, CDCl3): dia-
stereomeric mixture: δ = 16.0 (d, J = 6.1 Hz), 16.1 (d, J = 6.1 Hz),
Conclusions
The first organocatalytic asymmetric Michael addition of
β-oxo phosphonates to nitro olefins has been developed by
employing cinchonine-based thiourea 5a as the catalyst.
The corresponding adducts were obtained in good yields
with good to excellent enantioselectivities (up to 98% ee), 16.2 (t, J = 6.0 Hz), 30.5, 42.8 (d, J = 3.1 Hz), 43.2 (d, J = 3.6 Hz),
49.7 (d, J = 125.4 Hz), 50.6 (d, J = 127.6 Hz), 62.9 (d, J = 7.0 Hz),
63.2 (t, J = 7.3 Hz), 63.5 (d, J = 7.1 Hz), 77.4 (d, J = 7.2 Hz), 78.8,
127.8, 128.0, 128.2, 128.5, 128.6, 128.8, 128.9, 130.9, 133.3, 133.7,
137.0, 137.1, 137.3, 137.4, 137.5, 137.6, 194.2 (d, J = 5.8 Hz), 195.6
(d, J = 4.9 Hz) ppm; (R,R) diastereomer: δ = 16.0 (d, J = 6.1 Hz),
16.2 (d, J = 5.9 Hz), 43.1 (d, J = 3.8 Hz), 49.7 (d, J = 125.4 Hz),
63.2 (d, J = 6.9 Hz), 63.5 (d, J = 7.1 Hz), 78.7, 127.8, 127.9, 128.1,
128.4, 128.7, 133.3, 137.0, 137.1, 137.3, 194.1 (d, J = 5.7 Hz) ppm;
(R,S) diastereomer: δ = 15.9 (d, J = 6.0 Hz), 16.1 (d, J = 5.9 Hz),
42.8 (d, J = 3.2 Hz), 50.6 (d, J = 127.7 Hz), 62.9 (d, J = 7.0 Hz),
63.1 (d, J = 6.7 Hz), 77.4, 127.8, 128.1, 128.6, 128.9, 133.7, 137.4,
137.6, 137.7, 195.6 (d, J = 4.7 Hz) ppm. HRMS (ESI): calcd. for
C20H24NO6P [M + Na]+ 428.1234; found 428.1234. HPLC analysis
(Chiralpak OD-H column; hexane/2-propanol, 95:5; flow rate
1.0 mL/min; wavelength 220 nm): tr = 23.40 (minor,major isomer),
26.25 (major,major isomer), 33.56 (minor,minor isomer) and 60.84
(major,minor isomer) min.
albeit with poor diastereoselectivities due to the easily enol-
izable stereocenter at the α position with respect to the two
electron-withdrawing groups. This protocol facilitates ac-
cess to various enantioenriched α-substituted β-oxo phos-
phonate derivatives, potentially biologically active mole-
cules and valuable synthetic intermediates, starting from
readily available starting materials.
Experimental Section
General Methods: All reagents and solvents were commercial grade
and purified prior to use when necessary. NMR spectra were ac-
quired with a Bruker 400 MHz instrument. Chemical shifts were
measured relative to residual solvent peaks of CDCl3 as internal
standards (1H: δ = 7.26 ppm; 13C: δ = 77.0 ppm). Specific rotations
were measured with a Perkin–Elmer 341MC polarimeter. Enantio-
meric excesses were determined with an HP1-100 instrument (chiral
column; mobile phase: hexane/iPrOH). HRMS data were recorded
with a Varian QFT-ESI instrument. Melting points were deter-
mined with a Taike X-4 melting-point apparatus. Thioureas 1a,[14]
1b,[15] 1c,[16] 2a,[17] 2b,[5n] and 3–5a–d[18] were prepared according
to literature procedures.
Dimethyl
[(3R)-4-Nitro-1-oxo-1,3-diphenylbut-2-yl]phosphonate
(6b): White solid, 64 mg, 85% yield, m.p. 105–106 °C, [α]2D0 = +28.0
(c = 1.0, CHCl3), 1.6:1 dr, 37% ee for major diastereomer, 81% ee
1
for minor diastereomer. H NMR (400 MHz, CDCl3): δ = 3.49 (t,
J = 10.4 Hz, 2.30 H, CH3, major isomer), 3.64 (d, J = 11.2 Hz,
1.84 H, CH3, minor isomer), 3.74 (d, J = 10.8 Hz, 1.84 H, CH3,
minor isomer), 4.26–4.38 (m, 1 H, CH), 4.53–4.65 (m, 1 H, CH),
4.86 (dd, J = 10.8 and 13.2 Hz, 0.62 H, major isomer), 4.98 (dd, J
= 10.0 and 13.2 Hz, 0.38 H, minor isomer), 5.06 (dd, J = 4.0 and
13.2 Hz, 0.38 H, minor isomer), 5.18 (dd, J = 4.0 and 13.2 Hz, 0.61
H, major isomer), 7.07–7.09 (m, 3 H, aromatic), 7.15–7.21 (m, 2
H, aromatic), 7.28–7.50 (m, 3 H, aromatic), 7.60 (d, J = 7.6 Hz,
1.23 H, aromatic, major isomer), 7.72 (d, J = 7.6 Hz, 0.77 H, aro-
matic, minor isomer) ppm. 31P NMR (161.7 MHz, CDCl3): δ =
21.85, 22.04 ppm. 13C NMR (100.6 MHz, CDCl3): δ = 42.8 (d, J
= 3.2 Hz), 43.2 (d, J = 3.8 Hz), 49.3 (d, J = 126.1 Hz), 50.2 (d, J
= 128.4 Hz), 53.3 (d, J = 7.0 Hz), 53.4, 53.5 (d, J = 6.7 Hz), 53.6
(d, J = 6.5 Hz), 53.8 (d, J = 6.9 Hz), 77.2, 78.7, 127.8, 128.1, 128.2,
128.3, 128.5, 128.6, 128.7, 128.8, 129.0, 133.5, 133.9, 136.7, 136.9,
137.1, 137.2, 137.3, 137.4, 194.1 (d, J = 5.8 Hz), 195.4 (d, J =
5.0 Hz) ppm. HRMS (ESI): calcd. for C18H20NO6P [M + Na]+
400.0920; found 400.0919. HPLC analysis (Chiralpak AS-H col-
umn; hexane/2-propanol, 95:5; flow rate 1.0 mL/min; wavelength
220 nm): tr = 39.64 (major,major isomer), 44.69 (minor,major iso-
mer), 50.06 (major,minor isomer), 77.57 (minor,minor isomer) min.
General Procedure for the Asymmetric Michael Addition of β-Oxo
Phosphonates to Nitro Olefins Catalyzed by Thiourea 5a: A solution
of thiourea 5a (22.6 mg, 0.04 mmol), β-oxo phosphonate
(0.4 mmol), and nitro olefin (0.2 mmol) in anhydrous THF
(0.6 mL) was stirred at 20 °C. After the reaction was complete (as
monitored by TLC), the mixture was purified by column
chromatography on silica gel (200–300 mesh; CH2Cl2/EtOAc, 30:1–
10:1) to afford the desired conjugate addition products 6.
Diethyl [(3R)-4-Nitro-1-oxo-1,3-diphenylbut-2-yl]phosphonate (6a):
White solid, 71 mg, 87% yield, m.p. 114–116 °C, [α]2D0 = +33.8 (c =
1.0, CHCl3), 1.5:1 dr, 73% ee for the (R,R) diastereomer, 70% ee
for the (R,S) diastereomer. 1H NMR (400 MHz, CDCl3): dia-
stereomeric mixture: δ = 1.01 (t, J = 6.8 Hz, 1.19 H, CH3, minor
isomer), 1.07–1.13 (m, 3 H, CH3), 1.26 (t, J = 6.8 Hz, 1.76 H, CH3,
major isomer), 3.76–4.17 (m, 4 H, 2 OCH2), 4.27–4.40 (m, 1 H,
CH), 4.52–4.63 (m, 1 H, CH), 4.83–5.26 (m, 2 H, NCH2), 7.00–
7.19 (m, 5 H, aromatic), 7.26–7.50 (m, 3 H, aromatic), 7.62 (d, J =
7.6 Hz, 1.16 H, aromatic, major isomer), 7.73 (d, J = 7.6 Hz, 0.76
H, aromatic, minor isomer) ppm; (R,R) diastereomer: δ = 1.14 (t,
Diethyl
[(3R)-3-(2-Chlorophenyl)-4-nitro-1-oxo-1-phenylbut-2-yl]-
phosphonate (6c): Colorless liquid, 76 mg, 86% yield, [α]2D0 = +46.0
(c = 1.0, CHCl3), 1.1:1 dr, 86% ee for major diastereomer, 87% ee
1
for minor diastereomer. H NMR (400 MHz, CDCl3): δ = 1.03 (t,
J = 6.8 Hz, 3 H, CH3), 1.31 (t, J = 6.8 Hz, 3 H, CH3), 4.02–4.22 J = 6.8 Hz, 1.50 H, CH3, major isomer), 1.08 (t, J = 6.8 Hz, 1.36
(m, 4 H, 2 OCH2), 4.39–4.46 (m, 1 H, CH), 4.66 (dd, J = 11.2 and
20.4 Hz, 1 H, CH), 4.93 (dd, J = 11.2 and 12.4 Hz, 1 H), 5.31 (dd,
J = 3.6 and 12.8 Hz, 1 H), 7.05–7.19 (m, 5 H, aromatic), 7.33 (t, J
= 7.6 Hz, 2 H, aromatic), 7.46 (t, J = 7.6 Hz, 1 H, aromatic), 7.68
(d, J = 7.6 Hz, 2 H, aromatic) ppm; (R,S) diastereomer: δ = 0.99
(t, J = 6.8 Hz, 3 H, CH3), 1.09 (t, J = 6.8 Hz, 3 H, CH3), 3.79–
H, CH3, minor isomer), 1.19 (t, J = 6.0 Hz, 3 H, CH3), 3.86–4.11
(m, 4 H, 2 OCH2), 4.75–5.04 (m, 2 H, 2 CH), 5.24–5.38 (m, 2 H,
NCH2), 7.00–7.20 (m, 4 H, aromatic), 7.30–7.35 (m, 2 H, aro-
matic), 7.44 (s, 1 H, aromatic), 7.67 (d, J = 7.6 Hz, 0.99 H, aro-
matic, major isomer), 7.75 (d, J = 6.8 Hz, 0.92 H, aromatic, minor
isomer) ppm. 31P NMR (161.7 MHz, CDCl3): δ = 18.80 (major
3.93 (m, 4 H, 2 OCH2), 4.28–4.31 (m, 1 H, CH), 4.54 (dd, J = 6.4 isomer), 19.36 (minor isomer) ppm. 13C NMR (100.6 MHz,
and 20.0 Hz, 1 H, CH), 5.01 (dd, J = 10.0 and 13.2 Hz, 1 H), 5.09 CDCl3): δ = 15.9 (t, J = 5.0 Hz), 16.2 (t, J = 6.5 Hz), 38.9, 47.6 (d,
3510
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3507–3513

Synthesis of Optically Active β-Oxo Phosphonates
J = 126.3 Hz), 47.9 (d, J = 126.9 Hz), 63.0 (d, J = 7.0 Hz), 63.1 (d, mer), 3.83–4.22 (m, 4 H, 2 OCH2), 4.31–4.45 (m, H, CH), 4.55–
J = 6.7 Hz), 63.3 (d, J = 6.8 Hz), 63.5 (d, J = 7.0 Hz), 75.3 (d, J =
4.67 (m, 1 H, CH), 4.85–5.30 (m, 2 H, NCH2), 7.07–7.27 (m, 3 H,
6.0 Hz), 76.3, 127.0, 127.2, 128.3, 128.4, 128.5, 129.2, 130.4, 133.5, aromatic), 7.36–7.57 (m, 4 H, aromatic), 7.71 (d, J = 7.6 Hz, 1.20
133.6, 133.7, 134.4, 134.5, 194.1 (d, J = 5.6 Hz), 195.3 (d, J =
4.3 Hz) ppm. HRMS (ESI): calcd. for C20H23ClNO6P [M + Na]+
462.0844; found 462.0841. HPLC analysis (Chiralpak AD-H col-
umn; hexane/2-propanol, 95:5; flow rate 1.0 mL/min; wavelength
220 nm): tr = 40.11 (minor,minor isomer), 46.09 (major,minor iso-
mer), 49.92 (minor,major isomer), 61.72 (major,major isomer) min.
H, aromatic, major isomer), 7.83 (d, J = 7.6 Hz, 0.71 H, aromatic,
minor isomer) ppm. 31P NMR (161.7 MHz, CDCl3): δ = 18.75
(minor isomer), 18.83 ppm (major isomer) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 16.0 (t, J = 6.5 Hz), 16.1 (d, J = 6.1 Hz),
16.2 (d, J = 5.9 Hz), 29.6, 42.4 (d, J = 3.1 Hz), 42.5 (d, J = 3.5 Hz),
49.4 (d, J = 125.4 Hz), 50.3 (d, J = 127.4 Hz), 63.1 (d, J = 7.1 Hz),
63.2 (d, J = 7.2 Hz), 63.3 (d, J = 6.8 Hz), 63.6 (d, J = 7.1 Hz), 77.2,
78.5, 122.0, 122.2, 128.2, 128.6, 128.7, 129.5, 129.7, 131.9, 132.0,
133.6, 134.0, 136.2, 136.3, 136.5, 136.6, 137.0, 137.1, 193.7 (d, J
= 5.7 Hz), 195.2 (d, J = 4.9 Hz) ppm. HRMS (ESI): calcd. for
C20H23BrNO6P [M + Na]+ 506.0339; found 506.0334. HPLC
analysis (Chiralpak AS-H column; hexane/2-propanol, 90:10; flow
rate 1.0 mL/min; wavelength 220 nm): tr = 12.02 (minor,major iso-
mer), 17.05 (minor,minor isomer), 23.29 (major,minor isomer),
45.44 (major,major isomer) min.
Diethyl
[(3R)-3-(4-Chlorophenyl)-4-nitro-1-oxo-1-phenylbut-2-yl]-
phosphonate (6d): White solid, 75 mg, 85% yield, m.p. 119–121 °C,
[α]2D0 = +47.2 (c = 1.0, CHCl3), 1.7:1 dr, 74% ee for major dia-
stereomer, 72% ee for minor diastereomer. 1H NMR (400 MHz,
CDCl3): δ = 1.01 (t, J = 6.8 Hz, 1.15 H, CH3, minor isomer), 1.07–
1.13 (m, 3 H, CH3), 1.26 (t, J = 6.8 Hz, 1.95 H, CH3, major iso-
mer), 3.80–4.14 (m, 4 H, 2 OCH2), 4.29–4.40 (m, H, CH), 4.49–
4.61 (m, 1 H, CH), 4.79–5.25 (m, 2 H, NCH2), 7.07 (s, 2 H, aro-
matic), 7.13–7.20 (m, 2 H, aromatic), 7.30–7.39 (m, 2 H, aromatic),
7.44–7.53 (m, 1 H, aromatic), 7.65 (d, J = 8.0 Hz, 1.19 H, aromatic,
major isomer), 7.77 (d, J = 8.0 Hz, 0.72 H, aromatic, minor isomer)
ppm. 31P NMR (161.7 MHz, CDCl3): δ = 18.78 (major isomer),
18.87 (minor isomer) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
16.0 (t, J = 6.5 Hz), 16.2 (d, J = 5.9 Hz), 16.3 (d, J = 5.8 Hz), 29.6,
30.2, 42.3 (d, J = 3.2 Hz), 42.5 (d, J = 3.5 Hz), 49.5 (d, J =
125.4 Hz), 50.4 (d, J = 127.4 Hz), 63.0 (d, J = 7.0 Hz), 63.2 (d, J
= 6.9 Hz), 63.3 (d, J = 6.8 Hz), 63.7 (d, J = 7.1 Hz), 78.6 (d, J =
4.8 Hz), 125.5, 128.2, 128.6, 128.7, 129.0, 129.1, 129.2, 129.3, 133.6,
133.8, 134.0, 134.1, 135.6, 135.8, 136.0, 136.1, 137.2, 193.8 (d, J
= 5.8 Hz), 195.3 (d, J = 4.8 Hz) ppm. HRMS (ESI): calcd. for
C20H23ClNO6P [M + Na]+ 462.0844; found 462.0841. HPLC analy-
sis (Chiralpak AS-H column; hexane/2-propanol, 90:10; flow rate
1.0 mL/min; wavelength 220 nm): tr = 11.58 (minor,major isomer),
16.02 (minor,minor isomer), 21.73 (major,minor isomer), 42.73
(major,major isomer).
Diethyl
[(3R)-4-Nitro-1-oxo-1-phenyl-3-[3-(trifluoromethyl)phen-
yl]but-2-yl]phosphonate (6g): Colorless liquid, 80 mg, 85% yield,
[α]2D0 = +22.4 (c = 1.0, CHCl3), 1.3:1 dr, 61% ee for major isomer,
1
61% ee for minor isomer. H NMR (400 MHz, CDCl3): δ = 0.96
(t, J = 6.8 Hz, 1.32 H, CH3, minor isomer), 1.06–1.11 (m, 3 H,
CH3), 1.24 (t, J = 6.8 Hz, 1.77 H, CH3, major isomer), 3.74–4.16
(m, 4 H, 2 OCH2), 4.36–4.47 (m, H, CH), 4.53–4.66 (m, 1 H, CH),
4.85–5.29 (m, 2 H, NCH2), 7.18–7.51 (m, 7 H, aromatic), 7.62 (d,
J = 7.6 Hz, 1.12 H, aromatic, major isomer), 7.79 (d, J = 7.6 Hz,
0.85 H, aromatic, minor isomer) ppm. 31P NMR (161.7 MHz,
CDCl3): δ = 18.55 (minor isomer), 18.82 (major isomer) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 15.8 (d, J = 6.2 Hz), 16.0 (t, J =
5.6 Hz), 16.2 (d, J = 5.7 Hz), 29.6, 42.7 (d, J = 2.9 Hz), 42.9 (d, J
= 3.6 Hz), 49.3 (d, J = 126.5 Hz), 50.1 (d, J = 128.3 Hz), 63.0 (d,
J = 7.1 Hz), 63.2 (d, J = 6.7 Hz), 63.3 (d, J = 6.7 Hz), 63.7 (d, J =
7.1 Hz), 77.1, 77.2, 78.3, 122.2, 122.3, 124.5 (q, J = 3.6 Hz), 124.8
(q, J = 3.7 Hz), 125.0 (t, J = 3.8 Hz), 128.1, 128.5, 128.6, 128.7,
129.3, 129.4, 130.8, 130.9, 131.1, 131.2, 131.5, 131.7, 133.4, 134.0,
137.0, 138.2, 138.3, 138.4, 138.5, 193.9 (d, J = 5.9 Hz), 195.1 (d, J
= 4.9 Hz) ppm. HRMS (ESI): calcd. for C21H23F3NO6P [M +
Na]+ 496.1107; found 496.1104. HPLC analysis (Chiralpak
AD-H column; hexane/2-propanol, 95:5; flow rate 1.0 mL/
min; wavelength 220 nm): tr = 17.85 (minor,major isomer), 23.22
(minor,major isomer), 31.53 (minor,minor isomer), 61.14
(major,minor isomer) min.
Diethyl
[(3R)-3-(2-Bromophenyl)-4-nitro-1-oxo-1-phenylbut-2-yl]-
phosphonate (6e): Pale-yellow liquid, 83 mg, 86% yield, [α]2D0
=
+57.2 (c = 1.0, CHCl3), 1.4:1 dr, 86% ee for major diastereomer,
1
86% ee for minor diastereomer. H NMR (400 MHz, CDCl3): δ =
1.10 (t, J = 6.8 Hz, 1.73 H, CH3, major isomer), 1.15 (t, J = 6.8 Hz,
1.27 H, CH3, minor isomer), 1.27 (t, J = 6.8 Hz, 3 H, CH3), 3.90–
4.15 (m, 4 H, 2 OCH2), 4.81–5.04 (m, 2 H, 2 CH), 5.24–5.48 (m, 2
H, NCH2), 6.96–7.12 (m, 2 H, aromatic), 7.20–7.25 (m, 1 H, aro-
matic), 7.33–7.56 (m, 4 H, aromatic), 7.70 (d, J = 7.6 Hz, 1.18 H,
aromatic, major isomer), 7.84 (d, J = 6.0 Hz, 0.84 H, aromatic,
minor isomer) ppm. 31P NMR (161.7 MHz, CDCl3): δ = 18.76
(major isomer), 19.25 (minor isomer) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 15.9 (d, J = 6.1 Hz), 16.1 (d, J = 5.9 Hz), 16.2 (d, J =
5.9 Hz), 30.2, 41.1, 47.9 (d, J = 126.8 Hz), 63.0 (d, J = 7.0 Hz),
63.1, 63.4 (d, J = 6.8 Hz), 63.5 (d, J = 6.9 Hz), 75.3 (d, J = 4.8 Hz),
127.6, 127.8, 128.4, 128.5, 129.4, 133.4, 133.5, 133.5, 136.0, 136.4,
137.2, 194.1 (d, J = 5.6 Hz), 195.3 (d, J = 4.1 Hz) ppm. HRMS
(ESI): calcd. for C20H23BrNO6P [M + Na]+ 506.0339; found
506.0332. HPLC analysis (Chiralpak AS-H column; hexane/2-
Diethyl [(3R)-3-(2-Methoxyphenyl)-4-nitro-1-oxo-1-phenylbut-2-yl]-
phosphonate (6h): Colorless liquid, 73 mg, 84% yield, [α]2D0 = +54.8
(c = 1.0, CHCl3), 1.6:1 dr, 92% ee for major diastereomer, 92% ee
1
for minor diastereomer. H NMR (400 MHz, CDCl3): δ = 1.06 (t,
J = 7.2 Hz, 1.15 H, CH3, minor isomer), 1.13–1.19 (m, 3 H, CH3),
1.34 (t, J = 7.2 Hz, 1.84 H, CH3, major isomer), 3.71 (s, 1.76 H,
OCH3, major isomer), 3.76 (s, 1.07 H, OCH3, minor isomer), 3.84–
4.25 (m, 4 H, 2 OCH2), 4.39–4.48 (m, 0.61 H, CH, major isomer),
4.54–4.63 (m, 0.38 H, CH, minor isomer), 4.86–5.27 (m, 3 H, CH
and NCH2), 6.61–6.86 (m, 2 H, aromatic), 7.05–7.09 (m, 1 H, aro-
matic), 7.20–7.56 (m, 4 H, aromatic), 7.69 (d, J = 7.6 Hz, 1.14 H,
aromatic, major isomer), 7.83 (d, J = 7.2 Hz, 0.70 H, aromatic,
minor isomer) ppm. 31P NMR (161.7 MHz, CDCl3): δ = 20.10
(minor isomer), 20.53 (major isomer) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 15.9 (d, J = 6.4 Hz), 16.0 (d, J = 6.2 Hz), 16.2 (d, J =
6.0 Hz), 16.3 (d, J = 5.6 Hz), 30.2, 39.7, 41.9, 47.1 (d, J =
127.0 Hz), 47.4 (d, J = 128.4 Hz), 55.0, 55.1, 62.6 (d, J = 6.9 Hz),
62.9 (d, J = 6.7 Hz), 63.3 (d, J = 7.0 Hz), 75.9, 76.0, 110.8, 120.8,
123.7, 123.8, 124.8, 124.9, 125.4, 128.0, 128.3, 128.4, 128.6, 129.3,
129.4, 130.4, 132.2, 133.1, 133.5, 137.5, 137.6, 156.7, 157.1, 194.7
propanol, 93:7; flow rate 1.0 mL/min; wavelength 220 nm): tr
=
29.40 (minor,minor isomer), 31.08 (major,minor isomer), 37.26
(minor,major isomer), 41.48 (major,major isomer) min.
Diethyl
[(3R)-3-(4-Bromophenyl)-4-nitro-1-oxo-1-phenylbut-2-yl]-
phosphonate (6f): White solid, 80 mg, 83% yield, m.p. 128–130 °C,
[α]2D0 = +37.0 (c = 1.0, CHCl3), 1.7:1 dr, 68% ee for major dia-
stereomer, 68% ee for minor diastereomer. 1H NMR (400 MHz,
CDCl3): δ = 1.07 (t, J = 6.8 Hz, 1.26 H, CH3, minor isomer), 1.13–
1.19 (m, 3 H, CH3), 1.31 (t, J = 6.8 Hz, 2.17 H, CH3, major iso-
Eur. J. Org. Chem. 2011, 3507–3513
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3511

K. Hu, T. Liu, A. D. Lu, Y. Liu, Y. Wang, G. Wu, Z. Zhou, C. Tang
FULL PAPER
(d, J = 6.0 Hz), 195.4 (d, J = 5.0 Hz) ppm. HRMS (ESI): calcd. for
C21H26NO7P [M + Na]+ 458.1339; found 458.1340. HPLC analysis
(Chiralpak AD-H column; hexane/2-propanol, 95:5; flow rate
1.0 mL/min; wavelength 220 nm): tr = 39.77 (major,major isomer),
44.94 (minor,major isomer), 63.72 (minor,minor isomer), 159.88
(major,minor isomer) min.
ratory of Elemento-Organic Chemistry for generous financial sup-
port of our programs.
[1] For a review, see: P. Perlmutter, Conjugate addition reactions in
organic synthesis, Pergamon Press, Oxford, 1992.
[2] a) N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
New York, 2001; b) R. Ballini, M. Petrini, Tetrahedron 2004,
60, 1017–1047; c) C. Czekelius, E. M. Carreira, Angew. Chem.
Int. Ed. 2005, 44, 612–615.
[3] For reviews, see: a) A. M. Berner, L. Tedeschi, D. Enders, Eur.
J. Org. Chem. 2002, 1877–1894; b) S. B. Tsogoeva, Eur. J. Org.
Chem. 2007, 1701–1716.
[4] For the most recent examples of organocatalytic asymmetric
Michael addition reactions of aldehydes or aldehydes to nitro
olefins, see: a) A. Quintard, C. Bournaud, A. Alexakis, Chem.
Eur. J. 2008, 14, 7504–7507; b) P. García-García, A. Ladépêche,
R. Halder, B. List, Angew. Chem. Int. Ed. 2008, 47, 4719–4721;
c) Y. Hayashi, T. Itoh, M. Ohkubo, H. Ishikawa, Angew. Chem.
Int. Ed. 2008, 47, 4722–4724; d) M. Laars, K. Ausmees, M.
Uudsemaa, T. Tamm, T. Kanger, M. Lopp, J. Org. Chem. 2009,
74, 3772–3775; e) B. Han, Y. C. Xiao, Z. Q. He, Y. C. Chen,
Org. Lett. 2009, 11, 4660–4663; f) J. Wu, B. Ni, A. D. Headley,
Org. Lett. 2009, 11, 3354–3356; g) H. Uehara, C. F. Barbas III,
Angew. Chem. Int. Ed. 2009, 48, 9848–9852; h) Z. Zheng, B. L.
Perkins, B. Ni, J. Am. Chem. Soc. 2010, 132, 50–51.
[5] For the most recent examples of organocatalytic asymmetric
Michael addition reactions of aldehydes or ketones to nitro
olefins, see: a) Z. Yang, J. Liu, X. Liu, Z. Wang, X. Feng, Z.
Su, C. Hu, Adv. Synth. Catal. 2008, 350, 2001–2006; b) D. Q.
Xu, H. D. Yue, S. P. Luo, A. B. Xia, S. Zhang, Z. Y. Xu, Org.
Biomol. Chem. 2008, 6, 2054–2057; c) D.-Q. Xu, L.-P. Wang,
S.-P. Luo, Y.-F. Wang, S. Zhang, Z.-Y. Xu, Eur. J. Org. Chem.
2008, 1049–1053; d) T. Mandal, C. G. Zhao, Angew. Chem. Int.
Ed. 2008, 47, 7714–7717; e) L. Tuchman-Shukron, M. Portnoy,
Adv. Synth. Catal. 2009, 351, 541–546; f) X. Jiang, Y. Zhang,
A. S. C. Chan, R. Wang, Org. Lett. 2009, 11, 153–156; g) S.
Chandrasekhar, K. Mallikarjun, G. Pavankumarreddy, K. V.
Rao, B. Jagadeesh, Chem. Commun. 2009, 4985–4987; h) B.
Tan, X. Zeng, Y. Lu, P. J Chua, G. Zhong, Org. Lett. 2009, 11,
1927–1930; i) D.-Z. Xu, S. Shi, Y. Wang, Eur. J. Org. Chem.
2009, 4848–4853; j) J. Liu, Z. Yang, X. Liu, Z. Wang, Y. Liu,
S. Bai, L. Lin, X. Feng, Org. Biomol. Chem. 2009, 7, 4120–
4127; k) B. Ni, Q. Zhang, K. Dhungana, A. D. Headley, Org.
Lett. 2009, 11, 1037–1040; l) M. Freund, S. Schenker, S. B. Tso-
goeva, Org. Biomol. Chem. 2009, 7, 4279–4284; m) C.-M. Lo,
H.-F. Chow, J. Org. Chem. 2009, 74, 5181–5191; n) A. Lu, P.
Gao, Y. Wu, Y. Wang, Z. Zhou, C. Tang, Org. Biomol. Chem.
2009, 7, 3141–3147; o) X.-Q. Dong, H.-L. Teng, M.-C. Tong,
H. Huang, H.-Y. Tao, C.-J. Wang, Chem. Commun. 2010, 6840–
6842; p) B.-L. Li, Y.-F. Wang, S.-P. Luo, A.-G. Zhong, Z.-B.
Li, X.-H. Du, D.-Q. Xu, Eur. J. Org. Chem. 2010, 656–662; q)
H. Ma, K. Liu, F.-G. Zhang, C.-L. Zhu, J. Nie, J.-A. Ma, J.
Org. Chem. 2010, 75, 1402–1409; r) L. Peng, X.-Y. Xu, L.-L.
Wang, J. Huang, J.-F. Bai, Q.-C. Huang, L.-X. Wang, Eur. J.
Org. Chem. 2010, 1849–1853; s) A. Lu, R. Wu, Y. Wang, Z.
Zhou, G. Wu, J. Fang, C. Tang, Eur. J. Org. Chem. 2010, 2057–
2061; t) A. Lu, T. Liu, R. Wu, Y. Wang, Z. Zhou, G. Wu, J.
Fang, C. Tang, Eur. J. Org. Chem. 2010, 5777–5781; u) A. Lu,
R. Wu, Y. Wang, Z. Zhou, G. Wu, J. Fang, C. Tang, Eur. J.
Org. Chem. 2011, 122–127.
Diethyl [(3R)-3-(Naphthalen-1-yl)-4-nitro-1-oxo-1-phenylbut-2-yl]-
phosphonate (6i): Colorless liquid, 74 mg, 81% yield, [α]2D0 = +85.2
(c = 1.0, CHCl3), 1.3:1 dr, 98% ee for major diastereomer, 67% ee
1
for minor diastereomer. H NMR (400 MHz, CDCl3): δ = 1.04 (t,
J = 6.8 Hz, 1.91 H, CH3, major isomer), 1.12 (t, J = 6.8 Hz, 1.49
H, CH3, minor isomer), 1.18–1.23 (m, 3 H, CH3), 3.82–4.16 (m, 4
H, 2 OCH2), 4.69 (dd, J = 4.4 and 24.0 Hz, 0.52 H, CH, major
isomer), 4.91 (dd, J = 10.4 and 21.6 Hz, 0.41 H, CH, minor iso-
mer), 5.12–5.54 (m, 3 H, CH and NCH2), 7.13–7.27 (m, 4 H, aro-
matic), 7.32–7.40 (m, 3 H, aromatic), 7.45–7.80 (m, 4 H, aromatic),
8.15–8.22 (m, 1 H, aromatic) ppm. 31P NMR (161.7 MHz, CDCl3):
δ = 19.71 ppm. 13C NMR (100.6 MHz, CDCl3): δ = 16.0 (t, J =
6.4 Hz), 16.3 (t, J = 5.4 Hz), 29.6, 36.5, 49.4 (d, J = 127.8 Hz), 49.7
(d, J = 125.5 Hz), 63.1 (d, J = 6.9 Hz), 63.2, 63.3 (d, J = 6.8 Hz),
63.6 (d, J = 7.1 Hz), 76.1 (d, J = 3.9 Hz), 77.2, 78.5, 122.7, 123.7,
123.9, 124.8, 125.0, 126.0, 126.8, 127.1, 128.2, 128.3, 128.4, 128.7,
129.3, 130.6, 131.4, 133.2, 133.3, 133.6, 133.9, 134.2, 137.1, 137.4,
194.1 (d, J = 5.4 Hz), 195.8 (d, J = 4.0 Hz) ppm. HRMS (ESI):
calcd. for C24H26NO6P [M + Na]+ 478.1390; found 478.1395.
HPLC analysis (Chiralpak AS-H column; hexane/2-propanol,
90:10; flow rate 1.0 mL/min; wavelength 220 nm): tr = 12.97
(minor,minor isomer), 19.78 (major,minor isomer), 31.45
(minor,major isomer), 53.30 (major,major isomer) min.
Diethyl
[(3S)-3-(Furan-2-yl)-4-nitro-1-oxo-1-phenylbut-2-yl]phos-
phonate (6j): Colorless liquid, 66 mg, 84% yield, [α]2D0 = +21.6 (c =
1.0, CHCl3), 1:1 dr, 50% ee for major diastereomer, 94% ee for
minor diastereomer. 1H NMR (400 MHz, CDCl3): δ = 1.21–1.41
(m, 6 H, 2 CH3), 4.02–4.27 (m, 4 H, 2 CH2), 4.57–4.66 (m, 1 H,
CH), 4.83–4.93 (m, 1 H, CH), 5.04–5.14 (m, 1 H), 5.27 (dd, J =
3.2 and 13.6 Hz, 0.5 H), 5.34 (dd, J = 3.6 and 13.6 Hz, 0.48 H),
6.18–6.20 (m, 1 H, aromatic), 6.29–6.32 (m, 1 H, aromatic), 7.33
(s, 1 H, aromatic), 7.52 (d, J = 7.6 Hz, 1 H, aromatic), 7.56 (d, J
= 8.0 Hz, 1 H, aromatic), 7.63–7.69 (m, 1 H, aromatic), 7.93 (d, J
= 8.0 Hz, 1 H, aromatic), 7.97 (d, J = 8.0 Hz, 1 H, aromatic) ppm.
31P NMR (161.7 MHz, CDCl3): δ = 18.77, 18.92 ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 16.0 (d, J = 3.4 Hz), 16.1 (d, J = 3.7 Hz),
36.6 (d, J = 3.7 Hz), 37.2 (d, J = 3.3 Hz), 47.2 (d, J = 70.5 Hz),
48.4 (d, J = 71.7 Hz), 63.1 (d, J = 6.9 Hz), 63.3 (d, J = 6.7 Hz),
63.5 (d, J = 7.0 Hz), 75.9 (d, J = 7.2 Hz), 76.3, 128.4, 128.5, 128.6,
133.5, 133.8, 136.9, 137.1, 142.3, 142.5, 149.7 (d, J = 16.8 Hz),
150.5 (d, J = 12.2 Hz), 194.2 (d, J = 5.7 Hz), 194.9 (d, J = 4.5 Hz)
ppm. HRMS (ESI): calcd. for C18H22NO7P [M + Na]+ 418.1062;
found 418.1028. HPLC analysis (Chiralpak AD-H column; hexane/
2-propanol, 95:5; flow rate 1.0 mL/min; wavelength 220 nm): tr =
45.02 (minor,minor isomer), 47.19 (major,minor isomer), 51.44
(minor,major isomer), 102.98 (major,major isomer) min.
Supporting Information (see footnote on the first page of this arti-
cle): NMR, HRMS, and chiral HPLC data of the prepared op-
tically active acyclic α-substituted β-oxo phosphonates.
[6] For the most recent examples of organocatalytic asymmetric
Michael addition reactions of 1,3-dicarbonyl compounds to ni-
tro olefins, see: a) Y.-D. Ju, L. W. Xu, L. Li, G.-Q. Lai, H.-Y.
Qiu, J.-X. Jiang, Y. Lu, Tetrahedron Lett. 2008, 49, 6773–6777;
b) P. Gao, C. G. Wang, Y. Wu, Z. H. Zhou, C. Tang, Eur. J.
Org. Chem. 2008, 4563–4566; c) Z. Zhang, X.-Q. Dong, D.
Chen, C.-J. Wang, Chem. Eur. J. 2008, 14, 8780–8783; d) C.-J.
Wang, Z.-H. Zhang, X.-Q. Dong, X.-J. Wu, Chem. Commun.
2008, 1431–1433; e) F.-Z. Peng, Z.-H. Shao, B.-M. Fan, H.
Song, G.-P. Li, H.-B. Zhang, J. Org. Chem. 2008, 73, 5202–
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 20772058 and 20972070), the National Basic Research
Program of China (973 program 2010CB833300) and the Key labo-
3512
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3507–3513

Synthesis of Optically Active β-Oxo Phosphonates
5205; f) Z. Yu, X. Liu, L. Zhou, L. Lin, X. Feng, Angew. Chem.
Int. Ed. 2009, 48, 5195–5198; g) H. Li, L. Zu, H. Xie, W. Wang,
Synthesis 2009, 1525–1530; h) H. Li, S. Zhang, C. Yu, X. Song,
W. Wa n g , Chem. Commun. 2009, 2136–2138; i) J. Luo, L.-W.
Xu, R. A. S. Hay, Y. Lu, Org. Lett. 2009, 11, 437–440; j) P. G.
McGarraugh, S. E. Brenner, Tetrahedron 2009, 65, 449–455; k)
D. Diego, D. A. Alonso, E. Gómez-Bengoa, C. Nájera, J. Org.
Chem. 2009, 74, 6163–6168; l) X. Jiang, Y. Zhang, X. Liu, G.
Zhang, L. Lai, L. Wu, J. Zhang, R. Wang, J. Org. Chem. 2009,
74, 5562–5567; m) X. Han, J. Luo, C. Liu, Y. Lu, Chem. Com-
mun. 2009, 2044–2046; n) L. Zhang, M.-M. Lee, S.-M. Lee, J.
Lee, M. Cheng, B.-S. Jeong, H.-g. Park, S.-s. Jew, Adv. Synth.
Catal. 2009, 351, 3063–3066; o) Y. Oh, S. M. Kim, D. Y. Kim,
Tetrahedron Lett. 2009, 50, 4674–4676.
2005, 13, 69–75; e) S. K. Perumal, S. A. Adediran, R. F. Pratt,
Bioorg. Med. Chem. 2008, 16, 6987–6994.
[9] S. Delarue-Cochin, J.-J. Pan, A. Dauteloup, F. Hendra, R. G.
Angoh, D. Joseph, P. J. Stephensc, C. Cavéa, Tetrahedron:
Asymmetry 2007, 18, 685–691.
[10] Ł. Albrecht, B. Richter, C. Vila, H. Krawczyk, K. A.
Jørgensen, Chem. Eur. J. 2009, 15, 3093–3102.
[11] a) Y. Takemoto, Chem. Pharm. Bull. 2010, 58, 593–601; b) H.
Miyabe, Y. Takemoto, Bull. Chem. Soc. Jpn. 2008, 81, 785–
795; c) S. J. Connon, Chem. Commun. 2008, 2499–2510; d) S. J.
Connon, Chem. Eur. J. 2006, 12, 5418–5427.
[12] CCDC-817946 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[13] a) J.-A. Ma, D. Carhard, Angew. Chem. Int. Ed. 2004, 43, 4566–
4583; b) X. Xu, T. Furukawa, T. Okino, H. Miyabe, Y. Takem-
oto, Chem. Eur. J. 2006, 12, 466–476.
[14] B. Han, Q.-P. Liu, R. Li, X. Tian, X.-F. Xiong, J.-G. Deng, Y.-
C. Chen, Chem. Eur. J. 2008, 14, 8094–8097.
[15] T. Okino, A. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett.
2004, 6, 625–627.
[7] a) J. M. Varlet, N. Collignon, Tetrahedron 1981, 37, 3713–3721;
b) E. Zymanczyk-Duda, B. Lejczak, P. Kafarski, J. Grimaud,
P. Fischer, Tetrahedron 1995, 51, 11809–11814; c) M. Ordonez,
R. de la Cruz, M. Fernandez-Zertuche, M.-A. Munoz-Hernan-
dez, Tetrahedron: Asymmetry 2002, 13, 559–562; d) V. V. Nest-
erov, O. I. Kolodiazhnyi, Tetrahedron: Asymmetry 2006, 17,
1023–1026.
[8] a) S. Ladame, M. Bardet, J. Périé, M. Wilson, Bioorg. Med.
Chem. 2001, 9, 773–783; b) M. N. Greco, M. J. Hawkins, E. T. [16] C. Wang, Z. Zhou, C. Tang, Org. Lett. 2008, 10, 1707–1710.
Powell, H. R. Almond Jr., T. W. Corcoran, L. de Garavilla,
J. A. Kauffman, R. Recacha, D. Chattopadhyay, P. Andrade-
Gordon, B. E. Maryanoff, J. Am. Chem. Soc. 2002, 124, 3810–
3811; c) X. Li, A. Bhandari, C. P. Holmes, A. K. Szardenings,
Bioorg. Med. Chem. Lett. 2004, 14, 4301–4306; d) S. Bernier,
P.-M. Akochy, J. Lapointe, R. Chênevert, Bioorg. Med. Chem.
[17] C.-L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8,
2901–2904.
[18] B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett. 2005, 7,
1967–1969.
Received: January 10, 2011
Published Online: May 17, 2011
Eur. J. Org. Chem. 2011, 3507–3513
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3513